2. The compound of claim 1, wherein each -L- is independently selected
from the group consisting of --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3.

4. The compound of claim 1, wherein R3 is an optionally substituted aryl
group having from 1-4 optional substituents.

5. The compound of claim 4, wherein R3 is a optionally substituted phenyl
group and the 1-4 optional substituents are independently chosen from
halo, alkyl, alkoxy, haloalkyl, haloalkoxy, sulphonyl, and cyano.

6. The compound of claim 1, wherein R3 is an optionally substituted
arylalkoxy group having from 1-4 optional substituents.

7. The compound of claim 4, wherein R3 is an optionally substituted
benzyloxy group and the 1-4 optional substituents are independently
chosen from halo, alkyl, alkoxy, haloalkyl, haloalkoxy, sulphonyl, and
cyano.

30. A method for screening for an agent that inhibits LSD1 and/or LSD1
and MAO-B selectively compared to MAO-A comprising: (a) providing an
arylcyclopropylamine acetamide or derivative thereof (b) assaying the
arylcyclopropylamine acetamide or derivative thereof for its ability to
inhibit LSD1, MAO-B, and MAO-A (c) wherein an arylcyclopropylamine
acetamide or derivative thereof is a selective inhibitor of LSD1 and/or
LSD1 and MAO-B if the arylcyclopropylamine acetamide or derivative
thereof has an inhibitory constant for LSD1 or LSD1 and MAO-B that is at
least two-fold lower than the its inhibitory constant for MAO-A.

Description:

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of PCT Patent Application Serial
No. PCT/EP2009/063685, filed Oct. 19, 2009, and published in English as
International Patent Publication WO2010/043721 on Apr. 22, 2010, which
application claims priority to European Patent Application Serial No. EP
08166973.1 filed Oct. 17, 2008, and European Patent Application Serial
No. EP 09165840.1, filed Jul. 17, 2009, the entire disclosure of each of
which is hereby incorporated herein by this reference in its entirety.

TECHNICAL FIELD

[0002] The invention relates to compounds and their use in therapy.

BACKGROUND

[0003] Cancer is prevalent: there were about 3.2 million cancer cases
diagnosed (53% men, 47% women) and 1.7 million deaths from cancer (56%
men, 44% women) in Europe (Ferlay et al. (2007) Ann. Oncol.
18(3):581-92). In the United States, the probability of developing
invasive cancer is 38% for females and 46% for males that live to be 70
years old and older. In the US about 1.4 million new cases of cancer are
expected for 2006. Although the five year survival rate for cancer is now
65%, up from about 50% in the mid-nineteen seventies, cancer is deadly.
It is estimated that 565,000 people in the United States will die from
cancer in 2006 (American Cancer Society, Surveillance Research, 2006).
Despite tremendous advances in cancer treatment and diagnosis, cancer
remains a major public health concern. Accordingly, there is a need for
new therapeutics with activity in cancer.

[0004] Another health crisis is facing industrialized nations. As the
population in these countries age, neurodegenerative diseases are
affecting more and more people, posing a tremendous economic burden to
national health systems. Alzheimer's disease is the largest
neurodegenerative disease; disease modifying drugs have long been sought,
but to date, none have been identified. Other neurodegenerative
conditions include Parkinson's disease, Huntington's disease, Lewy Body
dementia, and which are all characterized by disease progression which
robs the patients of their ability to perform normal daily activities,
eventually leading to death.

[0005] One similar characteristic amongst many cancers and
neurodegenerative diseases is aberrant gene expression. A number of
compounds have been shown to alter gene expression, including histone
deacetylase inhibitors which alter the histone acetylation profile of
chromatin. Histone deacetylase inhibitors like SAHA, TSA, and many others
have been shown to alter gene expression in various in vitro and in vivo
animal models. Another modification that is involved in regulating gene
expression is histone methylation. Histones can be subject to numerous
modifications including lysine and arginine methylation. The methylation
status of histone lysines has recently been shown to be important in
dynamically regulating gene expression.

[0006] A group of enzymes known as histone lysine methyl transfeases and
histone lysine demethylases are involved histone lysine modifications.
One particular human histone lysine demethylase enzyme called Lysine
Specific Demethylase-1 (LSD1) was recently discovered (Shi et al. (2004)
Cell 119:941) to be involved in this crucial histone modification.
Inactivation of LSD1 in Drosophila (dLSD1) strongly affects the global
level of mono and dimethyl-H3-K4 methylation but not methyl-H3K9 while
the levels of some other histone methylation and acetylation marks
remained the same. dLSD1 inactivation resulted in elevated expression of
a subset of genes, including neuronal genes in non-neuronal cells
analogous to the functions of LSD1 in human cells. In Drosophila, dLsd1
is not an essential gene, but animal viability is strongly reduced in
mutant animals in a gender specific manner (Destefano et al. (2007) Curr
Biol. 17(9):808-12). Mouse homozygous LSD1 knock-outs were embryonic
lethal.

[0008] LSD1 is also involved in regulating the methylation of lysines of
some proteins which are not histones, like P53 and DNMT1 which both have
critical roles in cancer.

[0009] Lee et al. ((2006) Chem. Biol. 13:563-567) reported that
tranylcypromine inhibits histone H3K4 demethylation and can derepress
Egr1 gene expression in some cancer lines. A body of evidence is
accumulating that Egr-1 is a tumor suppressor gene in many contexts.
Calogero et al. ((2004) Cancer Cell International 4:1) reported that
Egr-1 is down-regulated in brain cancers and exogenous expression of
Egr-1 resulted in growth arrest and eventual cell death in primary cancer
cell lines. Lucerna et al. ((2006) Cancer Research 66, 6708-6713) showed
that sustained expression of Egr-1 causes antiangiogeneic effects and
inhibits tumor growth in some models. Ferraro et al. ((2005) J Clin
Oncol. March 20; 23(9):1921-6) reported that Egr-1 is down-regulated in
lung cancer patients with a higher risk of recurrence and may be more
resistant to therapy. Scoumanne et al. ((2007) J Biol Chem. May 25;
282(21):15471-5) observed that LSD1 is required for cell proliferation.
They found that deficiency in LSD1 leads to a partial cell cycle arrest
in G2/M and sensitizes cells to growth suppression induced by DNA damage.
Kahl et al. ((2006) Cancer Res. 66(23):11341-7) found that LSD1
expression is correlated with prostate cancer aggressiveness. Metzger et
al. ((2005) Nature 15; 437(7057):436-9) reported that LSD1 modulation by
siRNA and pargyline regulates androgen receptor (AR) and may have
therapeutic potential in cancers where AR plays a role, like prostate,
testis, and brain cancers. Thus, a body of evidence has implicated LSD1
in a number of cancers, which suggests that LSD1 is a therapeutic target
for cancer.

[0012] In view of the lack of adequate treatments for conditions such as
cancer, there is a desperate need for disease modifying drugs and drugs
that work by inhibiting novel targets. There is a need for the
development of LSD1 selective inhibitors particularly those which
selectively inhibit LSD1.

Disclosure

[0013] The present invention relates to the identification of compounds
and their use in treating and/or preventing diseases. The present
invention provides compounds of Formula I, pharmaceutical compositions
comprising a compound of Formula I and a pharmaceutically acceptable
carrier, and their use for treating diseases. One use of the compounds of
Formula I is for treating cancer. Another use for the compounds of
Formula I are to inhibit LSD1. Compounds of Formula I can have monoamine
oxidase inhibition activity and therefore can be used to treat diseases
like depression and Parkinson's disease as well as other
neurodegenerative conditions.

[0014] In one embodiment, the invention provides a compound of Formula I
or a pharmaceutically acceptable salt thereof:

[0024] Unless otherwise specified each L and each n in a molecule is
independently chosen and can be in either orientation, e.g.,
--(CH2)nNHC(═S)S(CH2)n--, refers to
phenylcyclopropylamine-(CH2)nNHC(═S)S(CH2)n-heter-
ocyclyl and phenylcyclopropylamine
--(CH2)nSC(═S)NH(CH2)n-heterocyclyl orientations.

[0025] In one aspect of this embodiment, each L is independently chosen
from --(CH2)n--NH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3, and the hydrocarbon portion is saturated. In
a specific aspect, each L is independently chosen from
--(CH2)n--(CH2)n-- and
--(CH2)nO(CH2)n where each n is independently chosen
from 0, 1, 2, and 3. In a more specific aspect of this embodiment, each L
is chosen from a bond, --CH2--, --CH2CH2--, --OCH2--,
--OCH2CH2--, --CH2OCH2--,
--CH2CH2CH2--, --OCH2CH2CH2--, and
--CH2OCH2CH2--. In an even more specific aspect, each L is
chosen from a bond, --CH2--, --CH2CH2--, OCH2--, and
--CH2CH2CH2--. In yet an even more specific aspect, L is
chosen from a bond and --CH2--.

[0027] In one aspect of this embodiment, if present, Rx and/or
Ry are independently chosen from --H, alkyl, alkynyl, alkenyl, and
-L-carbocyclyl, all of which are optionally substituted (except --H). In
an even more preferred specific aspect, the optional substituents are 1-4
optional substituents independently chosen from alkyl, alkenyl, alkynyl,
amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy,
halo, and cyano.

[0028] In another aspect of this embodiment, if present, Rz is an
optionally substituted heterocyclyl (i.e., -L-heterocyclyl where -L- is a
bond). In a more specific aspect of this embodiment, the optionally
substituted heterocyclyl has 1-4 optional substituents independently
chosen from alkyl, alkenyl, alkynyl, amino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, halo, and cyano. In an even more
specific aspect of the heterocyclyl has one substituent which is chosen
from alkyl and arylalkyl.

[0029] In a preferred aspect of this embodiment, when Rx and Ry
are present, one of Rx and Ry is hydro and the other of Rx
and Ry is chosen from alkyl, alkynyl, alkenyl, -L-carbocyclyl, all
of which are optionally substituted (except --H). In an even more
specific preferred aspect, the optional substituents are 1-4 optional
substituents independently chosen from alkyl, alkenyl, alkynyl, amino,
aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, halo, and
cyano.

[0030] In yet another preferred aspect of this embodiment, one of R2, R3,
and R4 is chosen from -L-aryl and -L-heterocyclyl wherein -L- is
independently chosen from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3; and the others of R2, R3, and R4 are chosen
from hydro, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6
haloalkoxy, and cyano. In a more specific preferred aspect, R1, R5, R6
and R7 are each hydro.

[0031] In one aspect of this embodiment, the invention provides a compound
of Formula I wherein R3 is an optionally substituted aryl group having
from 1-4 optional substituents. In a more specific aspect, R3 is an
optionally substituted phenyl group and the 1-4 optional substituents are
independently chosen from halo, alkyl, alkoxy, haloalkyl, haloalkoxy,
sulphonyl, and cyano. In a more specific aspect, R3 is an optionally
substituted phenyl group which has 1 or 2 optional substituents
independently chosen from halo, alkyl, alkoxy, haloalkyl, haloalkoxy,
sulphonyl, and cyano.

[0032] In one aspect of this embodiment, the invention provides a compound
Formula I, wherein R3 is an optionally substituted arylalkoxy group
having from 1-4 optional substituents. In a more specific aspect, R3 is
an optionally substituted benzyloxy group and the 1-4 optional
substituents are independently chosen from halo, alkyl, alkoxy,
haloalkyl, haloalkoxy, sulphonyl, and cyano. In a more specific aspect,
R3 is an optionally substituted benzyloxy group which has 1 or 2 optional
substituents independently chosen from halo, alkyl, alkoxy, haloalkyl,
haloalkoxy, sulphonyl, and cyano.

[0042] In one aspect of this embodiment, each L is independently chosen
from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3, and the hydrocarbon portion is saturated. In
a specific aspect, each L is independently chosen from
--(CH2)n--(CH2)n-- and
--(CH2)nO(CH2)n where each n is independently chosen
from 0, 1, 2, and 3. In a more specific aspect of this embodiment, each L
is chosen from a bond, --CH2--, --CH2CH2--,
--OCH2CH2--, --CH2OCH2--,
--CH2CH2CH2--, --OCH2CH2CH2--, and
--CH2OCH2CH2--. In an even more specific aspect, each L is
chosen from a bond, --CH2--, --CH2CH2--, OCH2--, and
--CH2CH2CH2--. In yet an even more specific aspect, L is
chosen from a bond and --CH2--.

[0044] In one aspect of this embodiment, Rx and/or Ry are
independently chosen from --H, alkyl, alkynyl, alkenyl, -L-carbocyclyl,
all of which are optionally substituted (except --H). In an even more
preferred specific aspect, the optional substituents are 1-4 optional
substituents independently chosen from alkyl, alkenyl, alkynyl, amino,
aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, halo, and
cyano. In one preferred aspect, Rx and Ry do not have optional
substituents.

[0045] In a preferred aspect of this embodiment, one of Rx and
Ry is hydro and the other of Rx and Ry is chosen from
alkyl, alkynyl, alkenyl, -L-carbocycle, all of which are optionally
substituted (except --H). In an even more specific preferred aspect, the
optional substituents are 1-4 optional substituents independently chosen
from alkyl, alkenyl, alkynyl, amino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, halo, and cyano. In one preferred
aspect, Rx and Ry do not have optional substituents.

[0046] In yet another preferred aspect of this embodiment one of R2, R3,
and R4 is chosen from -L-aryl and -L-heterocyclyl wherein -L- is
independently chosen from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3; and the others of R2, R3, and R4 are chosen
from hydro, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6
haloalkoxy, and cyano. In a more specific preferred aspect, R1, R5, R6
and R7 are each hydro.

[0051] R8 is --C(═O)NRxRy; [0052] Rx is chosen from
--H, C1-C6 alkyl, C2-C6 alkynyl, C2-C6 alkenyl, -L-carbocyclyl, -L-aryl,
-L-heterocyclyl, all of which are optionally substituted (except --H);
[0053] Ry is chosen from --H, C1-C6 alkyl, C2-C6 alkynyl, C2-C6
alkenyl, -L-carbocyclyl, -L-aryl, -L-heterocyclyl, all of which are
optionally substituted (except --H); [0054] each L is a linker that links
the main scaffold of Formula I to a carbocyclyl, heterocyclyl, or aryl
group, wherein the hydrocarbon portion of the linker -L- is saturated,
partially saturated, or unsaturated, and is independently chosen from a
saturated parent group having a formula of
--(CH2)n--(CH2)n--,
--(CH2)nC(═O)(CH2)n--,
--(CH2)nC(═O)NH(CH2)n--,
--(CH2)nNHC(═O)O(CH2)n--,
--(CH2)nNHC(═O)N(CH2)n--,
--(CH2)nNHC(═S)S(CH2)n--,
--(CH2)nOC(═O)S(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--,
--(CF12)nS(CH2)n--, and
--(CH2)nNHC(═S)NH(CH2)n--, where each n is
independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, and 8; and
pharmaceutically acceptable salts thereof.

[0056] In one aspect of this embodiment, each L is independently chosen
from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3, and the hydrocarbon portion is saturated. In
a specific aspect, each L is independently chosen from
--(CH2)n--(CH2)n-- and
--(CH2)nO(CH2)n where each n is independently chosen
from 0, 1, 2, and 3. In a more specific aspect of this embodiment, each L
is chosen from a bond, --CH2--, --CH2CH2--, --OCH2--,
--OCH2CH2--, --CH2OCH2--,
--CH2CH2CH2--, --OCH2CH2CH2--, and
--CH2OCH2CH2--. In an even more specific aspect, each L is
chosen from a bond, --CH2--, --CH2CH2--, OCH2--, and
--CH2CH2CH2--. In yet an even more specific aspect, L is
chosen from a bond and --CH2--.

[0058] In one aspect of this embodiment, Rx and/or Ry are
independently chosen from --H, alkyl, alkynyl, alkenyl, -L-carbocyclyl,
all of which are optionally substituted (except --H). In an even more
preferred specific aspect, the optional substituents are 1-4 optional
substituents independently chosen from alkyl, alkenyl, alkynyl, amino,
aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, halo, and
cyano. In one preferred aspect of this embodiment, Rx and Ry do
not have substituents.

[0059] In a preferred aspect of this embodiment, one of Rx and
Ry is hydro and the other of Rx and Ry is chosen from
alkyl, alkynyl, alkenyl, -L-carbocyclyl, all of which are optionally
substituted (except --H). In an even more specific preferred aspect, the
1-4 optional substituents are independently chosen from alkyl, alkenyl,
alkynyl, amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, halo, and cyano. In one preferred aspect, Rx and Ry do
not have substituents.

[0060] In one embodiment, the invention provides a compound of Formula I
or a pharmaceutically acceptable salt thereof wherein: [0061] each of
R1-R5 is optionally substituted and independently chosen from --H, halo,
alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heteroaryl, -L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy,
alkylthio, cycloalkylthio, alkynyl, amino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocarbonyl,
thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl,
O-thiocarbamyl, N-thiocarbamyl, and C-amido; [0062] R6 is chosen from --H
and C1-C6 alkyl; [0063] R7 is chosen from --H, alkyl, and cycloalkyl;
[0064] R8 is --C(═O)Rz; [0065] Rz is chosen from --H, C1-C6
alkoxy, -L-carbocyclyl, -L-heterocyclyl, and -L-aryl, all of which are
optionally substituted (except --H); [0066] each L is a linker that links
the main scaffold of Formula I to a carbocyclyl, heterocyclyl, or aryl
group, wherein the hydrocarbon portion of the linker -L- can be
saturated, partially saturated, or unsaturated, and is independently
chosen from a saturated parent group having a formula of
--(CH2)n--(CH2)n--,
--(CH2)nC(═O)(CH2)n--,
--(CH2)nC(═O)NH(CH2)n--,
--(CH2)nNHC(═O)O(CH2)n--,
--(CH2)nNHC(═O)NH(CH2)n--,
--(CH2)nNHC(═S)S(CH2)n--,
--(CH2)nOC(═O)S(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--,
--(CH2)nS(CH2)n--, and
--(CH2)nNHC(═S)NH(CH2)n--, where each n is
independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, and 8.

[0068] In one aspect of this embodiment, each L is independently chosen
from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3, and the hydrocarbon portion is saturated. In
a specific aspect, each L is independently chosen from
--(CH2)n--(CH2)n-- and
--(CH2)nO(CH2)n where each n is independently chosen
from 0, 1, 2 and 3. In a more specific aspect of this embodiment, each L
is chosen from a bond, --CH2--, --CH2CH2--, --OCH2--,
--OCH2CH2--, --CH2OCH2--,
--CH2CH2CH2--, --OCH2CH2CH2--, and
--CH2OCH2CH2--. In an even more specific aspect, each L is
chosen from a bond, --CH2--, --CH2CH2--, OCH2--, and
--CH2CH2CH2--. In yet an even more specific aspect, L is
chosen from a bond and --CH2--.

[0070] In another aspect of this embodiment, Rz is an optionally
substituted heterocyclyl (i.e., -L-heterocyclyl where -L- is a bond). In
a more specific aspect of this embodiment, the optionally substituted
heterocyclyl has 1-4 optional substituents which are independently chosen
from alkyl, alkenyl, alkynyl, amino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, halo, and cyano. In an even more
specific aspect of the heterocyclyl has 1 optional substituent which is
chosen from alkyl and arylalkyl.

[0071] In yet another preferred aspect of this embodiment one of R2, R3,
and R4 is chosen from -L-aryl and -L-heterocyclyl wherein -L- is
independently chosen from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3; and the others of R2, R3, and R4 are chosen
from hydro, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6
haloalkoxy, and cyano. In a more specific preferred aspect, R1, R5, R6
and R7 are each hydro.

[0072] In one embodiment, the invention provides a compound of Formula I
or a pharmaceutically acceptable salt thereof wherein: [0073] each of
R1-R5 is optionally substituted and independently chosen from hydro,
hydroxyl, halo, alkyl, alkenyl, alkynyl, alkoxy, arylalkyl, arylalkoxy,
haloalkyl, haloalkoxy, --N(C1-3 alkyl)2, --NH(C1-3 alkyl),
--C(═O)NH2, --C(═O)NH(C1-3 alkyl),
--C(═O)N(C1-3 alkyl)2, --S(═O)2(C1-3alkyl),
--S(═O)2NH2, --S(O)2N(C1-3 alkyl)2,
--S(═O)2NH(C1-3 alkyl), --CHF2, --OCF3,
--OCHF2, --SCF3, --CF3, --CN, --NH2, and --NO2;
[0074] R6 is chosen from --H and C1-C6 alkyl; [0075] R7 is chosen from
--H, alkyl, and cycloalkyl; [0076] R8 is --C(═O)Rz; [0077]
Rz is chosen from --H, -L-carbocyclyl, -L-heterocyclyl, -L-aryl,
wherein the aryl, heterocyclyl, or carbocycle is optionally substituted;
[0078] each L is a linker that links the main scaffold of Formula I to a
carbocyclyl, heterocyclyl, or aryl group, wherein the hydrocarbon portion
of the linker -L- is saturated, partially saturated, or unsaturated, and
is independently chosen from a saturated parent group having a formula of
--(CH2)n--(CH2)n--,
--(CH2)nC(═O)(CH2)n--,
--(CH2)nC(═O)NH(CH2)n--,
--(CH2)nNHC(═O)O(CH2)n--,
--(CH2)nNHC(═O)NH(CH2)n--,
--(CH2)nNHC(═S)S(CH2)n--,
--(CH2)nOC(═O)S(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--,
--(CH2)nS(CH2)n--, and
--(CH2)nNHC(═S)NH(CH2)n--, where each n is
independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, and 8; and
pharmaceutically acceptable salts thereof.

[0080] In one aspect of this embodiment, each L is independently chosen
from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3, and the hydrocarbon portion is saturated. In
a specific aspect, each L is independently chosen from
--(CH2)n--(CH2)n-- and
--(CH2)nO(CH2)n where each n is independently chosen
from 0, 1, 2, and 3. In a more specific aspect of this embodiment, each L
is chosen from a bond, --CH2--, --CH2CH2--, --OCH2--,
--OCH2CH2--, --CH2OCH2--,
--CH2CH2CH2--, --OCH2CH2CH2--, and
--CH2OCH2CH2--. In an even more specific aspect, each L is
chosen from a bond, --CH2--, --CH2CH2--, OCH2--, and
--CH2CH2CH2--. In yet an even more specific aspect, L is
chosen from a bond and --CH2--.

[0082] In another aspect of this embodiment, Rz is an optionally
substituted heterocyclyl (i.e., -L-heterocyclyl where -L- is a bond). In
a more specific aspect of this embodiment, the optionally substituted
heterocyclyl has 1-4 optional substituents which are independently chosen
from alkyl, alkenyl, alkynyl, amino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, halo, and cyano. In an even more
specific aspect of the heterocyclyl has 1 optional substituent which is
chosen from alkyl and arylalkyl.

[0083] In yet another preferred aspect of this embodiment one of R2, R3,
and R4 is chosen from -L-aryl and -L-heterocyclyl wherein -L- is
independently chosen from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3; and the others of R2, R3, and R4 are chosen
from hydro, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6
haloalkoxy, and cyano. In a more specific preferred aspect, R1, R5, R6
and R7 are each hydro.

[0084] In one preferred embodiment, the invention provides a compound of
Formula I(a), a pharmaceutical composition comprising a compound of
Formula I(a) and a pharmaceutically acceptable carrier, and/or methods
for treating diseases by administering to an individual a pharmaceutical
composition comprising a compound of Formula I(a). The compounds of
Formula I(a) are a sub-group of the compounds of Formula I wherein R6 is
hydro and R8 is --(C═O)Rz and the other variables are as defined
below in the following embodiments and aspects of the embodiments.

[0085] Thus, in a preferred embodiment, the invention provides a compound
of Formula I(a) or a pharmaceutically acceptable salt thereof

##STR00002##

wherein [0086] R1 is chosen from hydro, halo, C1-C6 alkyl, C1-C6
alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and cyano; [0087] one of R2,
R3, and R4 is chosen from -L-aryl and -L-heterocyclyl wherein -L- is
independently chosen from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3, and wherein the aryl or heterocyclyl moeity
of the -L-aryl and -L-heterocyclyl group is optionally substituted with
one group chosen from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl,
C1-C6 haloalkoxy, and cyano; [0088] and the others of R2, R3, and R4 are
independently chosen from hydro, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6
haloalkyl, C1-C6 haloalkoxy, cyano, and amino; [0089] R5 is chosen from
hydro, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6
haloalkoxy, and cyano;

[0092] In a specific aspect of this embodiment, each L is independently
chosen from --(CH2)n--(CH2)n-- and
--(CH2)nO(CH2)n where each n is independently chosen
from 0, 1, 2, and 3. In a more specific aspect of this embodiment, each L
is chosen from a bond, --CH2--, --CH2CH2--, --OCH2--,
--OCH2CH2--, --CH2OCH2--,
--CH2CH2CH2--, --OCH2CH2CH2--, and
--CH2OCH2CH2--. In an even more specific aspect, each L is
chosen from a bond, --CH2--, --CH2CH2--, OCH2--, and
--CH2CH2CH2--. In yet an even more specific aspect, L is
chosen from a bond and --CH2--.

[0093] In a more specific aspect of this embodiment, the invention
provides a compound of Formula I(a) wherein the optional substituents on
the heterocyclyl of Rz are independently chosen from alkyl, alkenyl,
amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, and
aryloxy. In an even more specific aspect, the heterocyclyl of Rz has
one optional substituent which is chosen from alkyl and arylalkyl.

[0094] In an even more specific aspect, the invention provides a compound
of Formula I(a) wherein the optional substituents on the ring system of
Rz are independently chosen from C1-C6 alkyl and arylalkyl wherein
the alkyl moiety of the arylalkyl group is a C1-C6 alkyl.

[0095] In one aspect of this embodiment, the invention provides a compound
of Formula I(a) wherein: [0096] R1 and R5 are hydro; [0097] one of R2,
R3, and R4 is chosen an -L-aryl group wherein the -L- is independently
chosen from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3; wherein the aryl moiety of the -L-aryl group
is optionally substituted with one group chosen from halo, C1-C6 alkyl,
C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and cyano; [0098] R7 is
hydro; [0099] Rz is an -L-heterocyclyl group wherein the
heterocyclyl is optionally substituted with 1-4 optional substituents and
the heterocyclyl group is chosen from morpholino, piperidyl, piperazinyl,
pyrrolidinyl, thiomorpholino, homopiperazinyl, imidazolyl,
imidazolidinyl, pyrazolidinyl, dioxanyl and dioxolanyl, and the -L- is
independently chosen from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
(CH2)nS(CH2)n--, wherein each n is independently
chosen from 0, 1, 2, and 3; o a pharmaceutically acceptable salts
thereof.

[0100] In a more specific aspect of this embodiment, the invention
provides compounds of Formula I(a) wherein the Rz is an
-L-heterocyclyl group wherein the -L- is a bond and the heterocyclyl is
optionally substituted with 1-4 optional substituents and the
heterocyclyl group is chosen from morpholino, piperidinyl, piperizinyl,
and pyrrolidinyl. In an even more specific aspect of this embodiment, the
1-4 optional are independently chosen from alkyl, alkenyl, amino, aryl,
arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, and aryloxy. In yet an
even more specific aspect of the heterocyclic group is chosen from
morpholino, piperidinyl, piperizinyl, and pyrrolidinyl and the
heterocyclyl has 1 optional substituent chosen from alkyl and arylalkyl.

[0101] In one aspect of this embodiment, -L- is --(CH2)r,
--(CH2)n-- or (CH2)nO(CH2)n, where each n
is independently chosen from 0, 1, 2, and 3.

[0102] In one aspect of this embodiment, the invention provides a compound
of Formula I(a) or a pharmaceutically acceptable salt thereof

wherein [0103] R1 and R5 are hydro; [0104] one of R2, R3, and R4 is
chosen from -L-aryl and -L-heterocyclyl wherein the -L- is independently
chosen from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3; and the others of R2, R3, and R4 are hydro,
and wherein the aryl or heterocyclyl moeity of the -L-aryl and
-L-heterocyclyl group is optionally substituted with one group chosen
from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy,
and cyano; [0105] R7 is hydro; [0106] Rz is a heterocyclyl group
(the -L- of -L-heterocyclyl is a bond) wherein the heterocyclyl is
optionally substituted with 1-4 optional substituents and the
heterocyclyl group is chosen from morpholino, piperidyl, piperazinyl,
pyrrolidinyl, homopiperazinyl; or a pharmaceutically acceptable salt
thereof.

[0107] In one aspect of this embodiment, the invention provides a compound
of Formula I(a) wherein: [0108] R1 and R2 are hydro; [0109] R3 is
-L-aryl wherein the -L- is independently chosen from
--(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3; and the others of R2, R3, and R4 are hydro,
and wherein the aryl moiety of the -L-aryl group is optionally
substituted with one group chosen from halo, C1-C6 alkyl, C1-C6 alkoxy,
C1-C6 haloalkyl, C1-C6 haloalkoxy, and cyano; [0110] R4 and R5 are hydro;
[0111] R7 is hydro; [0112] Rz is a heterocyclyl group (i.e., the -L-
of -L-heterocyclyl is a bond) wherein the heterocyclyl is optionally
substituted with 1-4 optional substituents and the heterocyclyl group is
chosen from morpholino, piperidyl, piperazinyl, pyrrolidinyl,
homopiperazinyl; or a pharmaceutically acceptable salts thereof.

[0113] In an even more specific aspect, the optionally substituted
heterocyclyl has one optional substituent chosen from alkyl and
arylalkyl.

[0114] In one aspect of this embodiment, the invention provides a compound
of Formula I(a) wherein R3 is an optionally substituted aryl group having
from 1-4 optional substituents. In a more specific aspect, R3 is an
optionally substituted phenyl group and the 1-4 optional substituents are
chosen from halo, alkyl, alkoxy, haloalkyl, haloalkoxy, sulphonyl, and
cyano. In a more specific aspect, R3 is an optionally substituted phenyl
group which has 1 or 2 optional substituents chosen from halo, alkyl,
alkoxy, haloalkyl, haloalkoxy, sulphonyl, and cyano.

[0115] In one aspect of this embodiment, the invention provides a compound
Formula I(a) wherein R3 is an optionally substituted arylalkoxy group
having from 1-4 optional substituents. In a more specific aspect, R3 is
an optionally substituted benzyloxy group and the 1-4 optional
substituents are chosen from halo, alkyl, alkoxy, haloalkyl, haloalkoxy,
sulphonyl, and cyano. In a more specific aspect, R3 is an optionally
substituted benzyloxy group which has 1 or 2 optional substituents
independently chosen from halo, alkyl, alkoxy, haloalkyl, haloalkoxy,
sulphonyl, and cyano.

[0116] In one embodiment, the invention provides a method of treating
and/or preventing a disease or condition comprising administering, to a
patient in need of treatment, a therapeutically effectively amount of a
composition comprising a compound of Formula I and a pharmaceutically
acceptable carrier. In one aspect of this embodiment, the invention
provides a compound of Formula I for use in treating and/or preventing a
disease or condition. In a related aspect, the invention provides for the
use of a compound of Formula I for the manufacture of a medicament for
treating and/or preventing a disease or condition. In a more specific
aspect of this embodiment, the compound of Formula I is a compound of
Formula I(a) as defined above.

[0117] In one embodiment, the invention provides a method of treating
and/or preventing cancer comprising administering, to a patient in need
of treatment, a therapeutically effectively amount of a composition
comprising a compound of Formula I and a pharmaceutically acceptable
carrier. In one aspect of this embodiment, the invention provides a
compound of Formula I for use in treating and/or preventing cancer. In a
related aspect, the invention provides for the use of a compound of
Formula I for the manufacture of a medicament for treating and/or
preventing cancer. In specific a specific aspect of the embodiments of
this paragraph, the cancer is chosen from breast cancer, colorectal
cancer, lung cancer, prostate cancer, testicular cancer, and brain
cancer. In a more specific aspect of this embodiment, the compound of
Formula I is a compound of Formula I(a) as defined above.

[0118] In one embodiment, the invention provides a method of inhibiting
LSD1 activity comprising administering, to a patient in need of
treatment, an amount of a composition comprising a compound of Formula I
and a pharmaceutically acceptable carrier sufficient to inhibit LSD1
activity. In one aspect of this embodiment, the invention provides a
compound of Formula I for use in inhibiting LSD1. In a related aspect,
the invention provides for the use of a compound of Formula I for the
manufacture of a medicament for inhibiting LSD1. In a more specific
aspect of this embodiment, the compound of Formula I is a compound of
Formula I(a) as defined above.

[0119] In one embodiment, the invention provides a method of inhibiting
monoamine oxidase activity comprising administering, to a patient in need
of treatment, an amount of a composition comprising a compound of Formula
I and a pharmaceutically acceptable carrier sufficient to inhibit
monoamine oxidase activity. In a related embodiment, the invention
provides a compound of Formula I for use in treating Parkinson's disease
and/or depression. In another related embodiment, the invention provides
for the use of a compound of Formula I for the manufacture of a
medicament for inhibiting monoamine oxidase. In one specific aspect of
this embodiment, the monoamine oxidase is MAO-B. In a more specific
aspect of this embodiment, the compound of Formula I is a compound of
Formula I(a) as defined above.

[0120] In one embodiment, the invention provides a method of treating
and/or preventing a neurodegenerative disease or disorder comprising
administering, to a patient in need of treatment, a therapeutically
effectively amount of a composition comprising a compound of Formula I
and a pharmaceutically acceptable carrier. In one aspect of this
embodiment, the invention provides a compound of Formula I for use in
treating and/or preventing a neurodegenerative disorder or condition. In
a related aspect, the invention provides for the use of a compound of
Formula I for the manufacture of a medicament for treating and/or
preventing a neurodegenerative disorder or condition. In a more specific
aspect of this embodiment, the compound of Formula I is a compound of
Formula I(a) as defined above.

[0121] The invention provides in some embodiments a pharmaceutical
composition comprising a pharmaceutically acceptable carrier and a
compound of Formula I which is selective inhibitors of LSD1. LSD1
selective inhibitors inhibit LSD1 to a greater extant than MAO-A and/or
MAO-B. Preferably, LSD1 selective inhibitors have IC50 values for LSD1
which are at least 2-fold lower than the IC50 value for MAO-A and/or
MAO-B. In one aspect of this embodiment, the LSD1 IC50 value is at least
5-fold lower than the IC50 value for MAO-A and/or MAO-B. In one aspect of
this embodiment, the LSD1 IC50 value is at least 10-fold lower than the
IC50 value for MAO-A and MAO-B. In one aspect of this embodiment, the
pharmaceutical composition comprising an LSD1 selective inhibitor and a
pharmaceutically acceptable salt thereof is useful for treating and/or
preventing a disease in an individual. In a more specific, the disease is
cancer. In an even more specific aspect, the disease is a cancer is
chosen from colorectal, breast, brain, prostate, lung, and testicular
cancer. In one specific aspect, the cancer is colorectal cancer. In one
specific aspect, the cancer is breast cancer. In one specific aspect, the
cancer is brain cancer. In one specific aspect, the cancer is prostate
cancer. In one specific aspect, the cancer is lung cancer. In one
specific aspect, the cancer is testicular cancer. In a more specific
aspect of this embodiment, the compound of Formula I is a compound of
Formula I(a) as defined above.

[0122] Unless otherwise defined, all technical and scientific terms used
herein have the same meaning as commonly understood by one of ordinary
skill in the art to which this invention pertains. Although methods and
materials similar or equivalent to those described herein can be used in
the practice or testing of the present invention, suitable methods and
materials are described below. In case of conflict, the present
specification, including definitions, will control. In addition, the
materials, methods, and examples are illustrative only and not intended
to be limiting.

[0123] Other features and advantages of the invention will be apparent
from the following detailed description, and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

[0124] The present invention relates to the identification of compounds
and their use in treating and/or preventing diseases. The present
invention provides compounds of Formula I, pharmaceutical compositions
comprising a compound of Formula I and a pharmaceutically acceptable
carrier, and their use for treating diseases. One use of the compounds of
Formula I is for treating cancer. Compounds of the invention are amine
oxidase inhibitors. Compounds of the invention are particularly potent
inhibitors of an amine oxidase known as Lysine Specific Demethylase 1 or
LSD1, which is a therapeutically relevant target. Compounds of the
invention also inhibit monoamine oxidases, and can therefore be used for
disease in which monoamine oxidase inhibition is useful. The compounds of
Formula I can be used as LSD1 selective inhibitors that inhibit LSD1 to a
greater extent than MAO-A and/or MAO-B. In particular it was found that
phenylcyclopropylamine derivatives of Formula I are compounds with
unexpectedly potent LSD1 inhibition. For example, most of the compounds
of Formula I in Table 1 of the examples have Ki (IC50) values for LSD1
inhibition under 10 micromolar which makes them more potent than
tranylcypromine for LSD1 inhibition. Furthermore, many of the compounds
of Table 1 have Ki (IC50) values for LSD1 inhibition of under 1
micromolar which makes them at least 20 to 30 fold more potent than
tranylcypromine. Surprisingly, some groups of compounds of this series
have been found to have IC50 values for LSD1 inhibition around or below
100 nanomolar. These compounds are LSD1 selective in that the inhibit
LSD1 to an extent greater than they inhibit MAO-A and/or MAO-B.

[0125] In one embodiment, the invention provides a compound of Formula I
or a pharmaceutically acceptable salt thereof:

[0129] R8 is chosen from --C(═O)NRxRy and
--C(═O)Rz; [0130] Rx is chosen from --H, alkyl, alkynyl,
alkenyl, -L-carbocyclyl, -L-aryl, and -L-heterocyclyl, all of which are
optionally substituted (except --H); [0131] Ry is chosen from --H,
alkyl, alkynyl, alkenyl, -L-carbocyclyl, -L-aryl, and -L-heterocyclyl,
all of which are optionally substituted (except --H); [0132] Rz is
chosen from --H, alkoxy, -L-carbocyclyl, -L-heterocyclyl, -L-aryl,
wherein the aryl, heteroaryl, heterocyclyl, or carbocyclyl are optionally
substituted; [0133] each L is a linker that links the main scaffold of
Formula I to a carbocyclyl, heterocyclyl, or aryl group, wherein the
hydrocarbon portion of the linker -L- is saturated, partially saturated,
or unsaturated, and is independently chosen from a saturated parent group
having a formula of --(CH2)n--(CH2)n--,
--(CH2)nC(═O)(CH2)n--,
--(CH2)nC(═O)NH(CH2)n--,
--(CH2)nNHC(═O)O(CH2)n--,
--(CH2)nNHC(═O)NH(CH2)n--,
--(CH2)nNHC(═S)S(CH2)n--,
--(CH2)nOC(═O)S(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)n--O(CH2)n--,
--(CH2)nS(CH2)n--, and
(CH2)nNHC(═S)NH(CH2)n--, where each n is
independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, and 8.

[0135] Unless otherwise specified each L and each n in a molecule is
independently chosen and is in either orientation, e.g.,
--(CH2)nNHC(═S)S(CH2)n--, refers to
phenylcyclopropylamine-(CH2)nNHC(═S)S(CH2)n-heter-
ocyclyl and phenylcyclopropylamine
--(CH2)nSC(═S)NH(CH2)n-heterocyclyl orientations.

[0136] A preferred configuration around the cyclopropyl ring of the
phenylcyclopropylamine derivatives of this embodiment is trans.

[0137] In one aspect of this embodiment, each L is independently chosen
from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3, and the hydrocarbon portion is saturated. In
a specific aspect, each L is independently chosen from
--(CH2)n--(CH2)n-- and
--(CH2)nO(CH2)n where each n is independently chosen
from 0, 1, 2, and 3. In a more specific aspect of this embodiment, each L
is chosen from a bond, --CH2--, --CH2CH2--, --OCH2--,
--OCH2CH2--, --CH2OCH2--,
--CH2CH2CH2--, --OCH2CH2CH2--, and
--CH2OCH2CH2--. In an even more specific aspect, each L is
chosen from a bond, --CH2--, --CH2CH2--, OCH2--, and
--CH2CH2CH2--. In yet an even more specific aspect, L is
chosen from a bond and --CH2--.

[0139] In one aspect of this embodiment, if present, Rz and/or
Ry are independently chosen from --H, alkyl, alkynyl, alkenyl, and
-L-carbocyclyl, all of which are optionally substituted (except --H). In
an even more preferred specific aspect, the optional substituents are 1-4
optional substituents independently chosen from alkyl, alkenyl, alkynyl,
amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy,
halo, and cyano.

[0140] In another aspect of this embodiment, if present, Rz is an
optionally substituted heterocyclyl (i.e., -L-heterocyclyl where -L- is a
bond). In a more specific aspect of this embodiment, the optionally
heterocyclyl has 1-4 optional substituents independently chosen from
alkyl, alkenyl, alkynyl, amino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, halo, and cyano. In an even more
specific aspect of the heterocyclyl has 1 optional substituent which is
chosen from alkyl and arylalkyl.

[0141] In a preferred aspect of this embodiment, when Rx and Ry
are present, one of Rx and Ry is hydro and the other of Rx
and Ry is chosen from alkyl, alkynyl, alkenyl, -L-carbocyclyl, all
of which are optionally substituted (except --H). In an even more
specific preferred aspect, the optional substituents are 1-4 optional
substituents independently chosen from alkyl, alkenyl, alkynyl, amino,
aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, halo, and
cyano.

[0142] In yet another preferred aspect of this embodiment, one of R2, R3,
and R4 is chosen from -L-aryl and -L-heterocyclyl wherein -L- is
independently chosen from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3; and the others of R2, R3, and R4 are chosen
from hydro, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6
haloalkoxy, cyano, and amino. In a more specific preferred aspect, R1,
R5, R6 and R7 are each hydro.

[0143] In one aspect of this embodiment, the invention provides a compound
of Formula I wherein R3 is an optionally substituted aryl group having
from 1-4 optional substituents. In a more specific aspect, R3 is an
optionally substituted phenyl group and the 1-4 optional substituents are
independently chosen from halo, alkyl, alkoxy, haloalkyl, haloalkoxy,
sulphonyl, and cyano. In a more specific aspect, R3 is an optionally
substituted phenyl group which has 1 or 2 optional substituents
independently chosen from halo, alkyl, alkoxy, haloalkyl, haloalkoxy,
sulphonyl, and cyano.

[0144] In one aspect of this embodiment, the invention provides a compound
Formula I, wherein R3 is an optionally substituted arylalkoxy group
having from 1-4 optional substituents. In a more specific aspect, R3 is
an optionally substituted benzyloxy group and the 1-4 optional
substituents are independently chosen from halo, alkyl, alkoxy,
haloalkyl, haloalkoxy, sulphonyl, and cyano. In a more specific aspect,
R3 is an optionally substituted benzyloxy group which has 1 or 2 optional
substituents independently chosen from halo, alkyl, alkoxy, haloalkyl,
haloalkoxy, sulphonyl, and cyano.

[0145] In one aspect of this embodiment, each of R1-R5 is independently
chosen from --H, halo, C1-C4 alkyl, C--C4 alkoxyl, C1-C4 haloalkyl,
--OCH2(phenyl), and C1-C4 haloalkoxy. In a more specific aspect,
each of R1-R5 is independently chosen from --H, halo, --OCH2(phenyl)
and --CF3. In a more specific aspect each of R1-R5 is --H.

[0146] In another aspect of this embodiment, R6 is --H or a C1-C4 alkyl.
In a more specific aspect, R6 is --H.

[0147] In yet another aspect of this embodiment, R7 is --H or a C1-C4
alkyl. In a more specific aspect, R7 is --H.

[0148] In another aspect of this embodiment, each L is chosen from a bond,
--CH2--, --CH2CH2--, and --CH2CH2CH2--. In
a more specific aspect, L is chosen from a bond and --CH2--.

[0149] In another aspect of this embodiment, Rx if present, is chosen
from --C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-aryl,
-L-heterocyclyl, wherein the cycloalkyl, aryl, and heterocyclyl is
optionally substituted. In a more specific aspect, Rx is chosen from
--H, --CH(CH3)2, --C(CH3)3,
--CH2CH═CH2, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, and --CH2(phenyl) wherein the cycloalkyl and phenyl
group are optionally substituted.

[0150] In another aspect of this embodiment, Ry if present, is chosen
from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-aryl,
-L-heterocyclyl, wherein the cycloalkyl, aryl, and heterocyclyl are
optionally substituted. In a more specific aspect, Ry is chosen from
--H, --CH(CH3)2, --C(CH3)3, --CH2C≡CH,
--CH2CH═CH2, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, and --CH2(phenyl), wherein the cycloalkyl and phenyl
group are optionally substituted.

[0151] In another aspect of this embodiment, z, if present, is an
optionally substituted -L-heterocyclyl. In a more specific aspect,
Rz is optionally substituted and chosen from N-methylpiperazinyl,
morpholinyl, and piperidinyl. In a more specific aspect, Rz is
chosen from N-methylpiperazinyl, morpholinyl, and piperidinyl.

[0161] A preferred configuration around the cyclopropyl ring of the
phenylcyclopropylamine derivatives of this embodiment is trans.

[0162] In one aspect of this embodiment, each L is independently chosen
from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3, and the hydrocarbon portion is saturated. In
a specific aspect, each L is independently chosen from
--(CH2)n--(CH2)n-- and
--(CH2)nO(CH2)n where each n is independently chosen
from 0, 1, 2, and 3. In a more specific aspect of this embodiment, each L
is chosen from a bond, --CH2--, --CH2CH2--, --OCH2--,
--OCH2CH2--, --CH2OCH2--,
--CH2CH2CH2--, --OCH2CH2CH2--, and
--CH2OCH2CH2--. In an even more specific aspect, each L is
chosen from a bond, --CH2--, --CH2CH2--, OCH2--, and
--CH2CH2CH2--. In yet an even more specific aspect, L is
chosen from a bond and --CH2--.

[0164] In one aspect of this embodiment, Rx and/or Ry are
independently chosen from --H, alkyl, alkynyl, alkenyl, -L-carbocyclyl,
all of which are optionally substituted (except --H). In an even more
preferred specific aspect, the optional substituents are 1-4 optional
substituents independently chosen from alkyl, alkenyl, alkynyl, amino,
aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, halo, and
cyano. In one preferred aspect, Rx and Ry do not have
substituents.

[0165] In a preferred aspect of this embodiment, when Rx and Ry
are present one of Rx and Ry is hydro and the other of Rx
and Ry is chosen from alkyl, alkynyl, alkenyl, -L-carbocycle, all of
which are optionally substituted (except --H). In an even more specific
preferred aspect, the optional substituents are 1-4 optional substituents
independently chosen from alkyl, alkenyl, alkynyl, amino, aryl,
arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, halo, and
cyano. In one preferred aspect, Rx and Ry do not have
substituents.

[0166] In yet another preferred aspect of this embodiment one of R2, R3,
and R4 is chosen from -L-aryl and -L-heterocyclyl wherein -L- is
independently chosen from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3; and the others of R2, R3, and R4 are chosen
from hydro, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6
haloalkoxy, cyano, and amino. In a more specific preferred aspect, R1,
R5, R6 and R7 are each hydro.

[0167] In one aspect of this embodiment, each of R1-R5 is independently
chosen from --H, halo, C1-C4 alkyl, C--C4 alkoxyl, C1-C4 haloalkyl,
--OCH2(phenyl), and C1-C4 haloalkoxy. In a more specific aspect,
each of R1-R5 is independently chosen from --H, halo,
--OCH2(phenyl), and --CF3. In a more specific aspect each of
R1-R5 is --H.

[0168] In another aspect of this embodiment, R6 is --H or a C1-C4 alkyl.
In a more specific aspect, R6 is --H.

[0169] In yet another aspect of this embodiment, R7 is --H or a C1-C4
alkyl. In a more specific aspect, R7 is --H.

[0170] In another aspect of this embodiment, each L is chosen from a bond,
--CH2--, --CH2CH2--, and --CH2CH2CH2--. In
a more specific aspect, L is chosen from a bond and --CH2--.

[0171] In another aspect of this embodiment, Rx if present, is chosen
from --H, --C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl,
-L-aryl, -L-heterocyclyl, wherein the cycloalkyl, aryl, and heterocyclyl
are optionally substituted. In a more specific aspect, Rx is chosen
from --H, --CH(CH3)2, --C(CH3)3,
--CH2C≡CH, --CH2CH═CH2, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, and --CH2(phenyl), wherein the cycloalkyl
and phenyl group are optionally substituted.

[0172] In another aspect of this embodiment, Ry if present, is chosen
from --H, --C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl,
-L-aryl, -L-heterocyclyl, wherein the cycloalkyl, aryl, and heterocyclyl
are optionally substituted. In a more specific aspect, Ry is chosen
from --H, --CH(CH3)2, --C(CH3)3,
--CH2C≡CH, --CH2CH═CH2, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, and --CH2(phenyl), wherein the cycloalkyl
and phenyl groups are optionally substituted.

[0173] In one embodiment, the invention provides a compound of Formula I
or a pharmaceutically acceptable salt thereof wherein: [0174] each of
R1-R5 is optionally substituted and independently chosen from hydro,
hydroxyl, halo, alkyl, alkenyl, alkynyl, alkoxy, arylalkyl, arylalkoxy,
haloalkyl, haloalkoxy, --N(C1-3 alkyl)2, --NH(C1-3 alkyl),
--C(═O)NH2, --C(═O)NH(C1-3 alkyl),
--C(═O)N(C1-3 alkyl)2, --S(═O)2(C1-3alkyl),
--S(═O)2NH2, --S(O)2N(C1-3 alkyl)2,
--S(═O)2NH(C1-3 alkyl), --CHF2, --OCF3,
--OCHF2, --SCF3, --CF3, --CN, --NH2, and --NO2;
[0175] R6 is chosen from --H and C1-C6 alkyl; [0176] R7 is chosen from
--H, alkyl, and cycloalkyl; [0177] R8 is --C(═O)NRxRy;
[0178] Rx is chosen from --H, C1-C6 alkyl, C2-C6 alkynyl, C2-C6
alkenyl, -L-carbocyclyl, -L-aryl, -L-heterocyclyl, all of which are
optionally substituted (except --H); [0179] Ry is chosen from --H,
C1-C6 alkyl, C2-C6 alkynyl, C2-C6 alkenyl, -L-carbocyclyl, -L-aryl,
-L-heterocyclyl, all of which are optionally substituted (except --H);
[0180] each L is a linker that links the main scaffold of Formula I to a
carbocyclyl, heterocyclyl, or aryl group, wherein the hydrocarbon portion
of the linker -L- is saturated, partially saturated, or unsaturated, and
is independently chosen from a saturated parent group having a formula of
--(CH2)n--(CH2)n--,
--(CH2)nC(═O)(CH2)n--,
--(CH2)nC(═O)NH(CH2)n--,
--(CH2)nNHC(═O)O(CH2)n--,
--(CH2)nNHC(═O)N(CH2)n--,
--(CH2)nNHC(═S)S(CH2)n--,
--(CH2)nOC(═O)S(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--,
--(CH2)nS(CH2)n--, and
--(CH2)nNHC(═S)NH(CH2)n--, where each n is
independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, and 8.

[0182] A preferred configuration around the cyclopropyl ring of the
phenylcyclopropylamine derivatives of this embodiment is trans.

[0183] In one aspect of this embodiment, each L is independently chosen
from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3, and the hydrocarbon portion is saturated. In
a specific aspect, each L is independently chosen from
--(CH2)n--(CH2)n-- and
--(CH2)nO(CH2)n where each n is independently chosen
from 0, 1, 2, and 3. In a more specific aspect of this embodiment, each L
is chosen from a bond, --CH2--, --CH2CH2--, --OCH2--,
--OCH2CH2--, --CH2OCH2--,
--CH2CH2CH2--, --OCH2CH2CH2--, and
--CH2OCH2CH2--. In an even more specific aspect, each L is
chosen from a bond, --CH2--, --CH2CH2--, OCH2--, and
--CH2CH2CH2--. In yet an even more specific aspect, L is
chosen from a bond and --CH2--.

[0185] In one aspect of this embodiment, Rx and/or Ry are
independently chosen from --H, alkyl, alkynyl, alkenyl, -L-carbocyclyl,
all of which are optionally substituted (except --H). In an even more
preferred specific aspect, the optional substituents are 1-4 optional
substituents independently chosen from alkyl, alkenyl, alkynyl, amino,
aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, halo, and
cyano. In one preferred aspect of this embodiment, Rx and Ry do
not have substituents.

[0186] In a preferred aspect of this embodiment, one of Rx and
Ry is hydro and the other of Rx and Ry is chosen from
alkyl, alkynyl, alkenyl, -L-carbocyclyl, all of which are optionally
substituted (except --H). In an even more specific preferred aspect, the
1-4 optional substituents are independently chosen from alkyl, alkenyl,
alkynyl, amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, halo, and cyano. In one preferred aspect, Rx and Ry do
not have substituents.

[0187] In one aspect of this embodiment, each of R1-R5 is independently
chosen from --H, halo, C1-C4 alkyl, C--C4 alkoxyl, C1-C4 haloalkyl,
--OCH2(phenyl), and C1-C4 haloalkoxy and --CF3. In a more
specific aspect, each of R1-R5 is independently chosen from --H, halo,
--OCH2(phenyl), and --CF3. In a more specific aspect each of
R1-R5 is --H.

[0188] In another aspect of this embodiment, R6 is --H or a C1-C4 alkyl.
In a more specific aspect, R6 is --H.

[0189] In yet another aspect of this embodiment, R7 is --H or a C1-C4
alkyl. In a more specific aspect, R7 is --H.

[0190] In another aspect of this embodiment, each L is chosen from a bond,
--CH2--, --CH2CH2--, and --CH2CH2CH2--. In
a more specific aspect, L is chosen from a bond and --CH2--.

[0191] In another aspect of this embodiment, Rx if present, is chosen
from --C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-aryl,
-L-heterocyclyl, wherein the cycloalkyl, aryl, and heterocyclyl are
optionally substituted. In a more specific aspect, Rx is chosen from
--H, --CH(CH3)2, --C(CH3)3, --CH2C≡CH,
--CH2CH═CH2, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, and --CH2(phenyl), wherein the cycloalkyl and phenyl
group are optionally substituted.

[0192] In another aspect of this embodiment, Ry if present, is chosen
from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-aryl,
-L-heterocyclyl, wherein the cycloalkyl, aryl, and heterocyclyl are
optionally substituted. In a more specific aspect, Ry is chosen from
--H, --CH(CH3)2, --C(CH3)3, --CH2C≡CH,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and --CH2(phenyl),
wherein the cycloalkyl and phenyl group are optionally substituted.

[0201] A preferred configuration around the cyclopropyl ring of the
phenylcyclopropylamine derivatives of this embodiment is trans.

[0202] In one aspect of this embodiment, each L is independently chosen
from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3, and the hydrocarbon portion is saturated. In
a specific aspect, each L is independently chosen from
--(CH2)n--(CH2)n-- and
--(CH2)nO(CH2)n where each n is independently chosen
from 0, 1, 2 and 3. In a more specific aspect of this embodiment, each L
is chosen from a bond, --CH2--, --CH2CH2--, --OCH2--,
--OCH2CH2--, --CH2OCH2--,
--CH2CH2CH2--, --OCH2CH2CH2--, and
--CH2OCH2CH2--. In an even more specific aspect, each L is
chosen from a bond, --CH2--, --CH2CH2--, OCH2--, and
--CH2CH2CH2--. In yet an even more specific aspect, L is
chosen from a bond and --CH2--.

[0204] In another aspect of this embodiment, Rz is an optionally
substituted heterocyclyl (i.e., -L-heterocyclyl where -L- is a bond). In
a more specific aspect of this embodiment, the optionally substituted
heterocyclyl has 1-4 optional substituents which are independently chosen
from alkyl, alkenyl, alkynyl, amino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, halo, and cyano. In an even more
specific aspect of the heterocyclyl has 1 optional substituent which is
chosen from alkyl and arylalkyl.

[0205] In yet another preferred aspect of this embodiment one of R2, R3,
and R4 is chosen from -L-aryl and -L-heterocyclyl wherein -L- is
independently chosen from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3; and the others of R2, R3, and R4 are chosen
from hydro, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6
haloalkoxy, cyano, and amino. In a more specific preferred aspect, R1,
R5, R6 and R7 are each hydro.

[0206] In one aspect of this embodiment, each of R1-R5 is independently
chosen from --H, halo, C1-C4 alkyl, C--C4 alkoxyl, C1-C4 haloalkyl,
--OCH2(phenyl), and C1-C4 haloalkoxy. In a more specific aspect,
each of R1-R5 is independently chosen from --H, halo,
--OCH2(phenyl), and --CF3. In a more specific aspect each of
R1-R5 is --H.

[0207] In another aspect of this embodiment, R6 is --H or a C1-C4 alkyl.
In a more specific aspect, R6 is --H.

[0208] In yet another aspect of this embodiment, R7 is --H or a C1-C4
alkyl. In a more specific aspect, R7 is --H.

[0209] In another aspect of this embodiment, each L is chosen from a bond,
--CH2--, --CH2CH2--, and --CH2CH2CH2--. In
a more specific aspect, L is chosen from a bond and --CH2--.

[0210] In another aspect of this embodiment, Rz if present is an
optionally substituted -L-heterocyclyl. In a more specific aspect,
Rz is optionally substituted and chosen from N-methylpiperazinyl,
morpholinyl, and piperidinyl. In a more specific aspect, Rz is
chosen from N-methylpiperazinyl, morpholinyl, and piperidinyl.

[0216] Rz is chosen from --H, -L-carbocyclyl, -L-heterocyclyl,
-L-aryl, wherein the aryl, heterocyclyl, or carbocycle is optionally
substituted; [0217] each L is a linker that links the main scaffold of
Formula I to a carbocyclyl, heterocyclyl, or aryl group, wherein the
hydrocarbon portion of the linker -L- is saturated, partially saturated,
or unsaturated, and is independently chosen from a saturated parent group
having a formula of --(CH2)n--(CH2)n--,
--(CH2)nC(═O)(CH2)n--,
--(CH2)nC(═O)NH(CH2)n--,
--(CH2)nNHC(═O)O(CH2)n--,
--(CH2)nNHC(═O)NH(CH2)n--,
--(CH2)nNHC(═S)S(CH2)n--,
--(CH2)nOC(═O)S(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--,
--(CH2)nS(CH2)n--, and
--(CH2)nNHC(═S)NH(CH2)n--, where each n is
independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, and 8; and
pharmaceutically acceptable salts thereof.

[0219] A preferred configuration around the cyclopropyl ring of the
phenylcyclopropylamine derivatives of this embodiment is trans.

[0220] In one aspect of this embodiment, each L is independently chosen
from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3, and the hydrocarbon portion is saturated. In
a specific aspect, each L is independently chosen from
--(CH2)n--(CH2)n-- and
--(CH2)nO(CH2)n where each n is independently chosen
from 0, 1, 2, and 3. In a more specific aspect of this embodiment, each L
is chosen from a bond, --CH2--, --CH2CH2--, --OCH2--,
--OCH2CH2--, --CH2OCH2--,
--CH2CH2CH2--, --OCH2CH2CH2--, and
--CH2OCH2CH2--. In an even more specific aspect, each L is
chosen from a bond, --CH2--, --CH2CH2--, OCH2--, and
--CH2CH2CH2--. In yet an even more specific aspect, L is
chosen from a bond and --CH2--.

[0222] In another aspect of this embodiment, Rz is an optionally
substituted heterocyclyl (i.e., -L-heterocyclyl where -L- is a bond). In
a more specific aspect of this embodiment, the optionally substituted
heterocyclyl has 1-4 optional substituents which are independently chosen
from alkyl, alkenyl, alkynyl, amino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, halo, and cyano. In an even more
specific aspect of the heterocyclyl has 1 optional substituent which is
chosen from alkyl and arylalkyl.

[0223] In yet another preferred aspect of this embodiment one of R2, R3,
and R4 is chosen from -L-aryl and -L-heterocyclyl wherein -L- is
independently chosen from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3; and the others of R2, R3, and R4 are chosen
from hydro, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6
haloalkoxy, and cyano. In a more specific preferred aspect, R1, R5, R6
and R7 are each hydro.

[0224] In one aspect of this embodiment, each of R1-R5 is independently
chosen from --H, halo, C1-C4 alkyl, C--C4 alkoxyl, C1-C4 haloalkyl,
--OCH2(phenyl), and C1-C4 haloalkoxy. In a more specific aspect,
each of R1-R5 is independently chosen from --H, halo,
--OCH2(phenyl), and --CF3. In a more specific aspect each of
each of R1-R5 is --H.

[0225] In another aspect of this embodiment, R6 is --H or a C1-C4 alkyl.
In a more specific aspect, R6 is --H.

[0226] In yet another aspect of this embodiment, R7 is --H or a C1-C4
alkyl. In a more specific aspect, R7 is --H.

[0227] In another aspect of this embodiment, each L is chosen from a bond,
--CH2--, --CH2CH2--, and --CH2CH2CH2--. In
a more specific aspect, L is chosen from a bond and --CH2--.

[0228] In another aspect of this embodiment, Rz if present, is an
optionally substituted -L-heterocyclyl. In a more specific aspect,
Rz is optionally substituted and chosen from N-methylpiperazinyl,
morpholinyl, and piperidinyl. In a more specific aspect, Rz is
chosen from N-methylpiperazinyl, morpholinyl, and piperidinyl.

[0229] In one preferred embodiment, the invention provides a compound of
Formula I(a), a pharmaceutical composition comprising a compound of
Formula I(a) and a pharmaceutically acceptable carrier, and/or a method
for treating diseases by administering to an individual a pharmaceutical
composition comprising a compound of Formula I(a).

[0230] The invention therefore provides a compound of Formula I(a) or a
pharmaceutically acceptable salt thereof:

[0237] In a related aspect, the invention provides a pharmaceutical
composition comprising a compound as defined in this paragraph and a
pharmaceutically acceptable carrier. In yet another related aspect, the
pharmaceutical composition, as described above, is used for treating
and/or preventing cancer.

[0238] A preferred configuration around the cyclopropyl ring of the
phenylcyclopropylamine derivatives of this embodiment is trans.

[0239] In a specific aspect of this embodiment, each L is independently
chosen from --(CH2)n--(CH2)n-- and
--(CH2)nO(CH2)n where each n is independently chosen
from 0, 1, 2, and 3. In a more specific aspect of this embodiment, each L
is chosen from a bond, --CH2--, --CH2CH2--, --OCH2--,
--OCH2CH2--, --CH2OCH2--,
--CH2CH2CH2--, --OCH2CH2CH2--, and
--CH2OCH2CH2--. In an even more specific aspect, each L is
chosen from a bond, --CH2--, --CH2CH2--, OCH2--, and
--CH2CH2CH2--. In yet an even more specific aspect, L is
chosen from a bond and --CH2--.

[0240] In a more specific aspect of this embodiment, the invention provide
a compound of Formula I(a) wherein the heterocyclyl of Rz is
optionally substituted with 1-4 optional substituents independently
chosen from alkyl, alkenyl, amino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, and aryloxy. In an even more specific aspect,
the heterocyclyl of Rz has one optional substituent which is chosen
from alkyl and arylalkyl.

[0241] In an even more specific aspect, the invention provides compounds
of Formula I(a) wherein the optional substituents on the ring system of
Rz are chosen from C1-C6 alkyl and arylalkyl wherein the alkyl
moiety of the arylalkyl group is a C1-C6 alkyl.

[0242] In one aspect of this embodiment, the invention provides a compound
of Formula I(a) or a pharmaceutically acceptable salt thereof wherein:
[0243] R1 and R5 are each hydro; [0244] one of R2, R3, and R4 is chosen
an -L-aryl group wherein the -L- is independently chosen from
--(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3; wherein the aryl moeity of the -L-aryl group
is optionally substituted with one group chosen from halo, C1-C6 alkyl,
C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, cyano, and amino; [0245]
R7 is hydro; [0246] Rz is an -L-heterocyclyl group wherein the
heterocyclyl is optionally substituted with 1-4 optional substituents and
the heterocyclyl group is chosen from morpholino, piperidyl, piperazinyl,
pyrrolidinyl, thiomorpholino, homopiperazinyl, imidazolyl,
imidazolidinyl, pyrazolidinyl, dioxanyl and dioxolanyl, and the -L- is
independently chosen from --(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
(CH2)nS(CH2)n--, wherein each n is independently
chosen from 0, 1, 2, and 3.

[0247] In a related aspect, the invention provides a pharmaceutical
composition comprising a compound as defined in this paragraph and a
pharmaceutically acceptable carrier. In yet another related aspect, the
pharmaceutical composition, as described above, can be used for treating
and/or preventing cancer.

[0248] In a more specific aspect of this embodiment, the invention
provides a compound of Formula I(a) wherein the Rz is an
-L-heterocyclyl group wherein the -L- is a bond and the heterocyclyl is
optionally substituted with 1-4 optional substituents and the
heterocyclyl group is chosen from morpholino, piperidinyl, piperizinyl,
and pyrrolidinyl. In an even more specific aspect of this embodiment, the
1-4 optional substituents are independently chosen from alkyl, alkenyl,
amino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, and
aryloxy. In yet an even more specific aspect of the heterocyclic group is
chosen from morpholino, piperidinyl, piperizinyl, and pyrrolidinyl and
the heterocyclyl has 1 optional substituent chosen from alkyl and
arylalkyl.

[0249] In one aspect of this embodiment, -L- is
--(CH2)n--(CH2)n-- or
(CH2)nO(CH2)n, where each n is independently chosen
from 0, 1, 2, and 3.

[0250] In one aspect of this embodiment, the invention provides a compound
of Formula I(a) or a pharmaceutically acceptbale salt thereof wherein:
[0251] R1 and R5 are hydro; [0252] one of R2, R3, and R4 is chosen from
-L-aryl and -L-heterocyclyl wherein the -L- is independently chosen from
--(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3; and the others of R2, R3, and R4 are hydro,
and wherein the aryl or heterocyclyl moeity of the -L-aryl and
-L-heterocyclyl group is optionally substituted with one group chosen
from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy,
and cyano; [0253] R7 is hydro; [0254] Rz is a heterocyclyl group
(the -L- of -L-heterocyclyl is a bond) wherein the heterocyclyl is
optionally substituted with 1-4 optional substituents and the
heterocyclyl group is chosen from morpholino, piperidyl, piperazinyl,
pyrrolidinyl, homopiperazinyl.

[0255] In a related aspect, the invention provides a pharmaceutical
composition comprising a compound as defined in this paragraph and a
pharmaceutically acceptable carrier. In yet another related aspect, the
pharmaceutical composition, as described above, is used for treating
and/or preventing cancer.

[0256] In one aspect of this embodiment, the invention provides a compound
of Formula I(a) or a pharmaceutically acceptable salt thereof wherein:
[0257] R1 and R2 are each hydro; [0258] R3 is -L-aryl wherein the -L- is
independently chosen from --(CH2)n--(CH2)n--,
--(CH2)nNH(CH2)n--,
--(CH2)nO(CH2)n--, and
--(CH2)nS(CH2)n--, where each n is independently
chosen from 0, 1, 2, and 3; and the others of R2, R3, and R4 are hydro,
and wherein the aryl moeity of the -L-aryl group is optionally
substituted with one group chosen from halo, C1-C6 alkyl, C1-C6 alkoxy,
C1-C6 haloalkyl, C1-C6 haloalkoxy, and cyano; [0259] R4 and R5 are each
hydro; [0260] R7 is hydro; [0261] Rz is a heterocyclyl group (i.e.,
the -L- of -L-heterocyclyl is a bond) wherein the heterocyclyl is
optionally substituted with 1-4 optional substituents and the
heterocyclyl group is chosen from morpholino, piperidyl, piperazinyl,
pyrrolidinyl, homopiperazinyl.

[0262] In an even more specific aspect, the heterocyclyl has one
substituent chosen from alkyl and arylalkyl. In a related aspect, the
invention provides a pharmaceutical composition comprising a compound as
defined in this paragraph and a pharmaceutically acceptable carrier. In
yet another related aspect, the pharmaceutical composition, as described
above, is used for treating and/or preventing cancer.

[0263] In one aspect of this embodiment, the invention provides a compound
of Formula I(a) wherein R3 is an optionally substituted aryl group having
from 1-4 optional substituents. In a more specific aspect, R3 is an
optionally substituted phenyl group and the 1-4 optional substituents are
independently chosen from halo, alkyl, alkoxy, haloalkyl, haloalkoxy,
sulphonyl, and cyano. In a more specific aspect, R3 is a optionally
substituted phenyl group which has 1 or 2 optional substituents
independently chosen from halo, alkyl, alkoxy, haloalkyl, haloalkoxy,
sulphonyl, and cyano.

[0264] In one aspect of this embodiment, the invention provides a compound
Formula I(a) wherein R3 is an optionally substituted arylalkoxy group
having from 1-4 optional substituents. In a more specific aspect, R3 is
an optionally substituted benzyloxy group and the 1-4 optional
substituents are independently chosen from halo, alkyl, alkoxy,
haloalkyl, haloalkoxy, sulphonyl, and cyano. In a more specific aspect,
R3 is an optionally substituted benzyloxy group which has 1 or 2 optional
substituents independently chosen from halo, alkyl, alkoxy, haloalkyl,
haloalkoxy, sulphonyl, and cyano.

[0266] In some of the embodiments of the invention related to compounds,
compositions and uses of compounds of Formula I, the compound does not
have the structure of the compounds having CAS registration nos.
928314-26-5 (Acetamide,
N,N-diphenyl-2-[[(1R,2S)-2-phenylcyclopropyl]amino]-), 917388-09-1
(4-Isoxazolecarboxamide,
N-[[[[3,5-dichloro-4-[[2-[[(1R,2S)-2-phenylcyclopropyl]amino]acetyl]amino-
]phenyl]methyl]amino]iminomethyl]-3-(4-methoxyphenyl)-5-methyl-),
825630-21-5 (Acetamide,
N-[4-[8-(methylamino)imidazo[1,2-a]pyrazin-3-yl]phenyl]-2-[(2-phenylcyclo-
propyl)amino]-), 728873-64-1 (Benzamide,
N-[(1S,2R)-2-hydroxy-1-[(hydroxyamino)carbonyl]propyl]-4-[[4-[[[[(1S,2R)--
2-phenylcyclopropyl]amino]acetyl]amino]phenyl]ethynyl]-(9CI)), and/or
728871-98-5 (Benzamide,
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-oxoethyl]-4-[[4-[[[[(1S,2R)-2--
phenylcyclopropyl]amino]acetyl]amino]phenyl]ethynyl]-(9CI)).
N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-oxoethyl]-4-({4-[({[(1S,2R)-2--
phenylcyclopropyl]amino}acetyl)amino]phenyl}ethynyl)benzamide;
N-{(1S,2R)-2-hydroxy-1-[(hydroxyamino)carbonyl]propyl}-4-({4-[({[(1S,2R)--
2-phenylcyclopropyl]amino}acetyl)amino]phenyl}ethynyl)benzamide;
N-[4-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-2-(2-phenyl-cyclo-
propylamino)-acetamide.

[0267] In one embodiment, the invention is a method for screening for an
agent that inhibits LSD1 and/or LSD1 and MAO-B selectively compared to
MAO-A comprising: [0268] (a) providing an arylcyclopropylamine
acetamide or derivative thereof [0269] (b) assaying the
arylcyclopropylamine acetamide or derivative thereof for its ability to
inhibit LSD1, MAO-B, and MAO-A [0270] (c) wherein an arylcyclopropylamine
acetamide or derivative thereof is a selective inhibitor of LSD1 and/or
LSD1 and MAO-B if the arylcyclopropylamine acetamide or derivative
thereof has an inhibitory constant for LSD1 or LSD1 and MAO-B that is at
least two-fold lower than the its inhibitory constant for MAO-A.

[0271] In one embodiment, the invention provides a method of treating
and/or preventing a disease or condition comprising administering, to a
patient in need of treatment, a therapeutically effectively amount of a
composition comprising a compound of Formula I and a pharmaceutically
acceptable carrier. In one aspect of this embodiment, the invention
provides a compound of Formula I for use in treating and/or preventing a
disease or condition. In a related aspect, the invention provides for the
use of a compound of Formula I for the manufacture of a medicament for
treating and/or preventing a disease or condition. In a more specific
aspect of this embodiment, the compound of Formula I is a compound of
Formula I(a) as defined above.

[0272] In one embodiment, the invention provides a method of treating or
preventing cancer comprising administering, to a patient in need of
treatment, a therapeutically effectively amount of a composition
comprising a compound of Formula I and a pharmaceutically acceptable
carrier. In one aspect of this embodiment, the invention provides a
compound of Formula I for use in treating and/or preventing cancer. In a
related aspect, the invention provides for the use of a compound of
Formula I for the manufacture of a medicament for treating and/or
preventing cancer. In one aspect of this embodiment, the cancer is breast
cancer, colorectal cancer, lung cancer, prostate cancer, testicular
cancer, or brain cancer. In a more specific aspect of this embodiment,
the compound of Formula I is a compound of Formula I(a) as defined above.

[0273] In one embodiment, the invention provides a method of inhibiting
LSD1 activity comprising administering, to a patient in need of
treatment, an amount of a composition comprising a compound of Formula I
and a pharmaceutically acceptable carrier sufficient to inhibit LSD1
activity. In one aspect of this embodiment, the invention provides a
compound of Formula I for use in inhibiting LSD1. In a related aspect,
the invention provides for the use of a compound of Formula I for the
manufacture of a medicament for inhibiting LSD1. In a more specific
aspect of this embodiment, the compound of Formula I is a compound of
Formula I(a) as defined above.

[0274] In one embodiment, the invention provides a method of treating
and/or preventing a neurodegenerative disease or disorder comprising
administering, to a patient in need of treatment, a therapeutically
effectively amount of a composition comprising a compound of Formula I
and a pharmaceutically acceptable carrier. In one aspect of this
embodiment, the invention provides a compound of Formula I for use in
treating and/or preventing a neurodegenerative disorder or condition. In
a related aspect, the invention provides for the use of a compound of
Formula I for the manufacture of a medicament for treating and/or
preventing a neurodegenerative disorder or condition. In a more specific
aspect of this embodiment, the compound of Formula I is a compound of
Formula I(a) as defined above.

[0275] The invention provides compounds of Formula I which are selective
inhibitors of LSD1 that inhibit LSD1 to a greater extent than MAO-A
and/or MAO-B. Preferably LSD1 selective inhibitors have IC50 values for
LSD1 which are at least 2-fold lower than the 1050 value for MAO-A and/or
MAO-B. In some embodiments, the LSD1 selective inhibitors have IC50
values which are at least 5-fold lower for LSD1 as compared to MAO-A and
MAO-B. In some embodiments, the LSD1 selective inhibitors have IC50
values which are at least 10-fold lower for LSD1 as compared to MAO-A and
MAO-B. In a more specific aspect of this embodiment, the compound of
Formula I is a compound of Formula I(a) as defined above.

[0283] Any definition herein may be used in combination with any other
definition to describe a composite structural group. By convention, the
trailing element of any such definition is that which attaches to the
parent moiety. For example, the composite group aryloxy would represent
an aryl group attached to the parent molecule through an oxy (--O--)
group, and the term arylalkyl would represent an aryl group attached to
the parent molecule through an alkyl group. The definitions defined
herein are intended as preferred definitions of the general art-accepted
meaning.

[0284] As used herein, the term "alkyl" refers to a saturated aliphatic
hydrocarbon including straight chain and branched chain groups. In a more
specific definition, the alkyl group has 1 to 20 carbon atoms (whenever
it appears herein, a numerical range such as "1 to 20" refers to each
integer in the given range; e.g., "1 to 20 carbon atoms" means that the
alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms,
etc. up to and including 20 carbon atoms). In another more specific
definition, it is a medium size alkyl having 1 to 10 carbon atoms. In yet
another more specific definition, it is a lower alkyl having 1 to 6
carbon atoms, and even more preferably 1 to 4 carbon atoms.

[0285] As used herein, the term "alkenyl" refers to an unsaturated
(including partially unsaturated) straight and branched chain hydrocarbon
having at one carbon carbon double bond. In a more specific definition,
the alkenyl group is further defined as having from 2 to 20 carbons. In a
more specific definition, the alkenyl group is further defined as having
from 2 to 10 carbons. In a more specific definition, the alkenyl group is
further defined as having from 2 to 6 carbons. In a more specific
definition, the alkenyl group is further defined as having from 2 to 4
carbons.

[0286] As used herein, the term "alkynyl" refers to an unsaturated
(including partially unsaturated) straight and branched chain hydrocarbon
having at one carbon carbon triple bond. In a more specific definition,
the alkynyl group is further defined as having from 2 to 20 carbons. In a
more specific definition, the alkynyl group is further defined as having
from 2 to 10 carbons. In a more specific definition, the alkynyl group is
further defined as having from 2 to 6 carbons. In a more specific
definition, the alkynyl group is further defined as having from 2 to 4
carbons.

[0287] As used herein, the term "acyl," refers to a carbonyl attached to
an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, or any
other moiety where the atom attached to the carbonyl is carbon.

[0288] As used herein, the term "acyloxy," refers to an acyl group
attached to the parent moiety through an oxygen atom.

[0289] As used herein, the term "halo" refers to chloro, fluoro, bromo,
and iodo.

[0290] As used herein, the term "hydro" refers to a hydrogen atom (--H
group).

[0291] As used herein, the term "hydroxy" refers to an --OH group.

[0292] As used herein, the term "alkoxy" refers to both an --O-alkyl and
an --O-cycloalkyl group, as defined herein. Lower alkoxy refers to
--O-lower alkyl groups.

[0293] As used herein, the term "aryloxy" refers to both an --O-aryl and
an --O-heteroaryl group, as defined herein.

[0294] As used herein, the term "mercapto" group refers to a --SH group.

[0295] As used herein, the term "alkylthio" group refers to an S-alkyl.

[0296] As used herein, the term "cycloalkylthio" refers to an
--S-cycloalkyl group.

[0297] As used herein, the term "arylthio" group refers to an --S-aryl.

[0298] As used herein, the term "carbonyl" group refers to a
--C(═O)R'' group, where R'' is selected from the group consisting of
hydro, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon)
and heterocyclic (bonded through a ring carbon), as defined herein.

[0299] As used herein, the term "aldehyde" group refers to a carbonyl
group where R'' is hydro.

[0300] As used herein, the term "cycloketone" refer to a cycloalkyl group
in which one of the carbon atoms which form the ring has a "═O"
bonded to it; i.e. one of the ring carbon atoms is a --C(═O)-group.

[0301] As used herein, the term "thiocarbonyl" group refers to a
--C(═S)R'' group, with R'' as defined herein.

[0302] As used herein, the term "O-carboxy" group refers to a
R''C(═O)O-group, with R'' as defined herein.

[0303] As used herein, the term "C-carboxy" group refers to a
--C(═O)OR'' groups with R'' as defined herein.

[0304] As used herein, the term "ester" is a C-carboxy group, as defined
herein, wherein R'' is any of the listed groups other than hydro.

[0305] As used herein, the term "C-carboxy salt" refers to a
--C(═O)O-M.sup.+ group wherein M.sup.+ is selected from the
group consisting of lithium, sodium, magnesium, calcium, potassium,
barium, iron, zinc and quaternary ammonium.

[0306] As used herein, the term "acetyl" group refers to a
--(C═O)CH3 group.

[0307] As used herein, the term "carboxyalkyl" refers to
--(CH2)rC(═O)OR'' wherein r is 1-6 and R'' is as defined
above.

[0308] As used herein, the term "carboxyalkyl salt" refers to a
--(CH2)rC(═O)O-M.sup.+ wherein M.sup.+ is selected
from the group consisting of lithium, sodium, potassium, calcium,
magnesium, barium, iron, zinc and quaternary ammonium.

[0309] As used herein, the term "carboxylic acid" refers to a C-carboxy
group in which R'' is hydro.

[0310] As used herein, the term "cycloalkoxy" refers and O-cycloalkyl
group.

[0311] As used herein, the term "haloalkyl" refers to an alkyl group
substituted with 1 to 6 halo groups. In a specific embodiment, haloalkyl
is a --CX3 group wherein X is a halo group. The halo groups can be
independently selected.

[0312] As used herein, the term "haloaryl" refers to an aryl group having
the meaning as defined above wherein one or more hydrogens are replaced
with a halogen.

[0313] As used herein, the term "heteroarylthio" refers to a --S--
heteroaryl group.

[0314] As used herein, the term "trihalomethanesulfonyl" refers to a
X3CS(═O)2-- group with X as defined above.

[0315] As used herein, the term "cyano" refers to a --C≡N group.

[0316] As used herein, the term "cyanato" refers to a --CNO group.

[0317] As used herein, the term "isocyanato" refers to a --NCO group.

[0318] As used herein, the term "thiocyanato" refers to a --CNS group.

[0319] As used herein, the term "isothiocyanato" refers to a --NCS group.

[0320] As used herein, the term "sulfinyl" refers to a --S(═O)R''
group, with R'' as defined herein.

[0321] As used herein, the term "sulfonyl" refers to a
--S(═O)2R'' group, with R'' as defined herein.

[0322] As used herein, the term "sulfonamido" refers to a
--S(═O)2 NR17R18, with R17 and R18 as
defined herein (independently selected from the group consisting of hydro
and lower alkyl).

[0323] As used herein, the term "trihalomethanesulfonamido" refers to a
X3CS(═O)2NR17-- group with X and R17 as defined
herein.

[0324] As used herein, the term "O-carbamyl" refers to a
--OC(═O)NR17R18 group with R17 and R18 as defined
herein.

[0325] As used herein, the term "N-carbamyl" refers to a
R18OC(═O)NR17-- group, with R17 and R18 as
defined herein.

[0326] As used herein, the term "O-thiocarbamyl" refers to a
--OC(═S)NR17R18 group with R17 and R18 as defined
herein.

[0327] As used herein, the term "N-thiocarbamyl" refers to a
R17O(C═S)NR18-- group, with R17 and R18 as
defined herein.

[0328] As used herein, the term "amino" refers to an --NRR group, with R
and R both being hydro.

[0329] As used herein, the term "C-amido" refers to a
--C(═O)NR17R18 group with R17 and R18 as defined
herein.

[0330] An "N-amido" refers to a R17C(═O)NR18-- group with
R17 and R18 as defined herein.

[0331] As used herein, the term "nitro" refers to a --NO2 group.

[0332] As used herein, the term "quaternary ammonium" refers to a
--NR17R18R19 group wherein R17, R18, and
R19 are independently selected from the group consisting of hydro
and lower alkyl.

[0333] As used herein, the term "methylenedioxy" refers to a
--OCH2O-- group wherein the oxygen atoms are bonded to adjacent ring
carbon atoms.

[0334] As used herein, the term "ethylenedioxy" refers to a
--OCH2CH2O-- group wherein the oxygen atoms are bonded to
adjacent ring carbon atoms.

[0335] As used herein, the term "carbocycle," "carbocyclic" or
"carbocyclyl" refers to an all-carbon monocyclic or fused ring (i.e.,
rings which share an adjacent pair of ring carbon atoms) group wherein
one or more of the rings does not have a completely conjugated
pi-electron system. Examples, without limitation, of carbocyclic groups
are "cycloalkyls" such as cyclopropane, cyclobutane, cyclopentane,
cyclohexane, adamantane, cycloheptane and cycloalkenes such as
cycloheptatriene, cyclopentene, and cyclohexadiene.

[0336] As used herein, the term "heterocyclyl," "heterocyclyl" or
"heterocyclic" refers to a saturated or partially saturated 3-7 membered
monocyclic, or 7-10 membered bicyclic ring system, which consists of
carbon atoms and from one to four heteroatoms independently selected from
the group consisting of O, N, and S, wherein the nitrogen and sulfur
heteroatoms can be optionally oxidized, the nitrogen can be optionally
quaternized, and including any bicyclic group in which any of the
above-defined heterocyclic rings is fused to a benzene ring, and wherein
the heterocyclic ring can be substituted on carbon or on a nitrogen atom
if the resulting compound is stable. Non-limiting saturated or partially
saturated heterocyclic groups include tetrahydrofuranyl, pyranyl,
piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl,
indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl,
chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl and tetramoyl groups.
Example of "heterocyclyls" or "heterocyclic" rings also include, but are
not limited to, morpholino, piperidyl, piperazinyl, pyrrolidinyl,
thiomorpholino, homopiperazinyl, imidazolyl, imidazolidinyl,
pyrazolidinyl, dioxanyl and dioxolanyl. "Heterocyclyl" can include
heteroaryls when the pi-electron system of a heterocyclyl is completely
conjugated.

[0337] As used herein, the term "aryl" refers to an all-carbon monocyclic
or fused-ring polycyclic (i.e., rings which share an adjacent pair of
ring carbon atoms) aromatic group having a completely conjugated
pi-electron system. Examples, without limitation, of aryl groups are
phenyl, naphthalenyl and anthracenyl.

[0338] As used herein, the term "heteroaryl" refers to a monocyclic or
fused ring polycyclic group having 5 to 14 ring atoms; 6, 10 or 14 pi
electrons shared in a cyclic array; and containing carbon atoms and 1, 2
or 3 heteroatoms independently selected from the group consisting of O,
N, and S. In a more specific definition, it refers to a monocyclic or
fused-ring polycyclic aromatic group having from 5 to 9 ring atoms and
comprising 1, 2, or 3 heteroatoms independently selected from the group
consisting of O, N, and S, Non-limiting examples of heteroaryl groups
include thienyl (thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl,
thianthrenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl,
phenoxanthiinyl, pyrrolyl, including without limitation 2H-pyrrolyl,
imidazolyl, pyrazolyl, pyridyl (pyridinyl), including without limitation
2-pyridyl, 3-pyridyl, and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,
4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl,
quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl,
phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl,
isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl,
7-aminoisocoumarin, pyrido[1,2-a]pyrimidin-4-one,
pyrazolo[1,5-a]pyrimidinyl, including without limitation
pyrazolo[1,5-a]pyrimidin-3-yl, 1,2-benzoisoxazol-3-yl, benzimidazolyl,
2-oxindolyl and 2 oxobenzimidazolyl. When the heteroaryl group contains a
nitrogen ring atom, such nitrogen ring atom may be in the form of an
N-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl
N-oxide.

[0339] As used herein, the term "arylalkyl" refers to any of the
C1-10 alkyl groups substituted by any of the above-mentioned
C6-14 aryl groups as defined herein. Non-limiting examples of
arylalkyl group include benzyl, phenethyl, and naphthylmethyl.

[0340] As used herein, the term "arylalkenyl" is used herein to mean any
of the above-mentioned C2-10 alkenyl groups substituted by any of
the above-mentioned C6-14 aryl groups.

[0341] As used herein, the term "arylalkynyl" refers to any of C2-10
alkynyl groups substituted by any of the above-mentioned C6-14 aryl
groups as defined herein.

[0342] As used herein, the term "arylalkoxy" refers to any of the
C1-10 alkoxy groups substituted by any of the aryl groups as defined
herein. Examples of arylalkoxy groups include benzyloxy and phenethyloxy.

[0343] As used herein, the term "aryloxy" refers to oxygen substituted by
any of the C6-14 aryl groups defined herein. Examples of aryloxy
groups include phenoxy and phenethoxy.

[0344] As used herein, the term "arylthio" group refers to a --S-aryl.

[0345] As used herein, the term "acyl" refers to a carbonyl attached to an
alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, or any other
moiety where the atom attached to the carbonyl is carbon.

[0346] As used herein, the term "acylamino" refers to an acyl group
attached to the parent moiety through an amino group.

[0347] As used herein, the term "acyloxy" refers to an acyl group attached
to the parent moiety through an oxygen atom.

[0348] As used herein, the term "preventing an increase in a symptom"
refers to both not allowing a symptom to increase or worsen, as well as
reducing the rate of increase in the symptom. For example, a symptom can
be measured as the amount of particular disease marker, i.e., a protein.
In another example the symptom can be cognitive decline. Preventing an
increase, according to the definition provided herein, means that the
amount of symptom (e.g., protein or cognitive decline) does not increase
or that the rate at which it increases is reduced.

[0349] As used herein, the term "treating a disease or disorder" refers to
a slowing of or a reversal of the progress of the disease. Treating a
disease or disorder includes treating a symptom and/or reducing the
symptoms of the disease.

[0350] As used herein, the term "preventing a disease or disorder" refers
to a slowing of the disease or of the onset of the disease or the
symptoms thereof. Preventing a disease or disorder can include stopping
the onset of the disease or symptoms thereof. As used herein, the term
"unit dosage form" refers to a physically discrete unit, such as a
capsule or tablet suitable as a unitary dosage for a human patient. Each
unit contains a predetermined quantity of a compound of Formula I, which
was discovered or believed to produce the desired pharmacokinetic profile
which yields the desired therapeutic effect. The dosage unit is composed
of a compound of Formula I in association with at least one
pharmaceutically acceptable carrier, salt, excipient, or combination
thereof.

[0351] As used herein, the term "dose" or "dosage" refers the amount of
active ingredient that an individual takes or is administered at one
time. For example, a 40 mg dose of a compound of Formula I refers to, in
the case of a twice-daily dosage regimen, a situation where the
individual takes 40 mg of a compound of Formula I twice a day, e.g., 40
mg in the morning and 40 mg in the evening. The 40 mg of a compound of
Formula I dose can be divided into two or more dosage units, e.g., two 20
mg dosage units of a compound of Formula I in tablet form or two 20 mg
dosage units of a compound of Formula I in capsule form.

[0352] As used herein, a "pharmaceutically acceptable prodrug" is a
compound that may be converted under physiological conditions or by
solvolysis to the specified compound or to a pharmaceutically acceptable
salt of such compound.

[0353] As used herein, a "pharmaceutically active metabolite" is intended
to mean a pharmacologically active product produced through metabolism in
the body of a specified compound or salt thereof. Metabolites of a
compound may be identified using routine techniques known in the art and
their activities determined using tests such as those described herein.

[0354] As used herein, a "pharmaceutically acceptable salt" is intended to
mean a salt that retains the biological effectiveness of the free acids
and bases of the specified compound and that is not biologically or
otherwise undesirable. A compound for use in the invention may possess a
sufficiently acidic, a sufficiently basic, or both functional groups, and
accordingly react with any of a number of inorganic or organic bases, and
inorganic and organic acids, to form a pharmaceutically acceptable salt.
Exemplary pharmaceutically acceptable salts include those salts prepared
by reaction of the compounds of the present invention with a mineral or
organic acid or an inorganic base, such as salts including sulfates,
pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,
monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates,
chlorides, bromides, iodides, acetates, propionates, decanoates,
caprylates, acrylates, formates, isobutyrates, caproates, heptanoates,
propiolates, oxalates, malonates, succinates, suberates, sebacates,
fumarates, maleates, butyne-1,4 dioates, hexyne-1,6-dioates, benzoates,
chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates,
methoxybenzoates, phthalates, sulfonates, xylenesulfonates,
phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates,
gamma-hydroxybutyrates, glycollates, tartrates, methane-sulfonates,
propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates,
and mandelates.

[0355] As used herein, a "pharmaceutically acceptable carrier" refers to a
non-API (API refers to Active Pharmaceutical Ingredient) substances such
as disintegrators, binders, fillers, and lubricants used in formulating
pharmaceutical products. They are generally safe for administering to
humans according to established governmental standards, including those
promulgated by the United States Food and Drug Administration and the
European Medical Agency.

[0356] As is understood by the skilled artisan, certain variables in the
list of substituents are repetitive (different name for the same
substituent), generic to other terms in the list, and/or partially
overlap in content with other terms. In the compounds of the invention,
the skilled artisan recognizes that substituents may be attached to the
remainder of the molecule via a number of positions and the preferred
positions are as illustrated in the Examples.

[0357] Additionally, the compounds of Formula I (and the compounds of
Formula I(a)) can contain asymmetric carbon atoms and can therefore exist
in racemic and optically active forms. Thus, optical isomers or
enantiomers, racemates, tautomers, and diastereomers are also encompassed
in the compounds of Formula I (and the compounds of Formula I(a)). The
methods of present invention include the use of all such isomers and
mixtures thereof. Methods of separation of enantiomeric and
diastereomeric mixtures are well known to one skilled in the art. The
present invention encompasses any isolated racemic or optically active
form of compounds described in Formula I (and the compounds of Formula
I(a)), or any mixture thereof. In one aspect, the compounds of the
invention have a trans configuration around the cyclopropyl ring as in
trans-phenylcyclopropylamine. In one aspect, the compounds of the
invention have a cis configuration around the cyclopropyl ring as in
cis-phenylcyclopropylamine. In a preferred aspect, the compounds of
Formula I (and the compounds of Formula I(a)) have the trans
configuration.

[0358] Typically, compounds according to Formula I (and the compounds of
Formula I(a)) can be effective at an amount of from about 0.01 μg/kg
to about 100 mg/kg per day based on total body weight. The active
ingredient may be administered at once, or may be divided into a number
of smaller doses to be administered at predetermined intervals of time.
The suitable dosage unit for each administration can be, e.g., from about
1 μg to about 2000 mg, preferably from about 5 μg to about 1000 mg.

[0359] It should be understood that the dosage ranges set forth above are
exemplary only and are not intended to limit the scope of this invention.
The therapeutically effective amount for each active compound can vary
with factors including but not limited to the activity of the compound
used, stability of the active compound in the patient's body, the
severity of the conditions to be alleviated, the total weight of the
patient treated, the route of administration, the ease of absorption,
distribution, and excretion of the active compound by the body, the age
and sensitivity of the patient to be treated, and the like, as will be
apparent to a skilled artisan. The amount of administration can be
adjusted as the various factors change over time.

[0360] For oral delivery, the active compounds can be incorporated into a
formulation that includes pharmaceutically acceptable carriers such as
binders (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g.,
starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide),
disintegrating agents (e.g., alginate, Primogel, and corn starch), and
sweetening or flavoring agents (e.g., glucose, sucrose, saccharin, methyl
salicylate, and peppermint). The formulation can be orally delivered in
the form of enclosed gelatin capsules or compressed tablets. Capsules and
tablets can be prepared in any conventional techniques. The capsules and
tablets can also be coated with various coatings known in the art to
modify the flavors, tastes, colors, and shapes of the capsules and
tablets. In addition, liquid carriers such as fatty oil can also be
included in capsules.

[0361] Suitable oral formulations can also be in the form of suspension,
syrup, chewing gum, wafer, elixir, and the like. If desired, conventional
agents for modifying flavors, tastes, colors, and shapes of the special
forms can also be included. In addition, for convenient administration by
enteral feeding tube in patients unable to swallow, the active compounds
can be dissolved in an acceptable lipophilic vegetable oil vehicle such
as olive oil, corn oil and safflower oil.

[0362] The active compounds can also be administered parenterally in the
form of solution or suspension, or in lyophilized form capable of
conversion into a solution or suspension form before use. In such
formulations, diluents or pharmaceutically acceptable carriers such as
sterile water and physiological saline buffer can be used. Other
conventional solvents, pH buffers, stabilizers, anti-bacteria agents,
surfactants, and antioxidants can all be included. For example, useful
components include sodium chloride, acetates, citrates or phosphates
buffers, glycerin, dextrose, fixed oils, methyl parabens, polyethylene
glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic
acid, and the like. The parenteral formulations can be stored in any
conventional containers such as vials and ampoules.

[0363] Routes of topical administration include nasal, bucal, mucosal,
rectal, or vaginal applications. For topical administration, the active
compounds can be formulated into lotions, creams, ointments, gels,
powders, pastes, sprays, suspensions, drops and aerosols. Thus, one or
more thickening agents, humectants, and stabilizing agents can be
included in the formulations. Examples of such agents include, but are
not limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum,
beeswax, or mineral oil, lanolin, squalene, and the like. A special form
of topical administration is delivery by a transdermal patch. Methods for
preparing transdermal patches are disclosed, e.g., in Brown, et al.
(1988) Ann. Rev. Med. 39:221-229 which is incorporated herein by
reference.

[0364] Subcutaneous implantation for sustained release of the active
compounds may also be a suitable route of administration. This entails
surgical procedures for implanting an active compound in any suitable
formulation into a subcutaneous space, e.g., beneath the anterior
abdominal wall. See, e.g., Wilson et al. (1984) J. Clin. Psych.
45:242-247. Hydrogels can be used as a carrier for the sustained release
of the active compounds. Hydrogels are generally known in the art. They
are typically made by crosslinking high molecular weight biocompatible
polymers into a network, which swells in water to form a gel like
material. Preferably, hydrogels are biodegradable or biosorbable. For
purposes of this invention, hydrogels made of polyethylene glycols,
collagen, or poly(glycolic-co-L-lactic acid) may be useful. See, e.g.,
Phillips et al. (1984) J. Pharmaceut. Sci., 73: 1718-1720.

[0365] The active compounds can also be conjugated, to a water soluble
non-immunogenic non-peptidic high molecular weight polymer to form a
polymer conjugate. For example, an active compound is covalently linked
to polyethylene glycol to form a conjugate. Typically, such a conjugate
exhibits improved solubility, stability, and reduced toxicity and
immunogenicity. Thus, when administered to a patient, the active compound
in the conjugate can have a longer half-life in the body, and exhibit
better efficacy. See generally, Burnham (1994) Am. J. Hosp. Pharm.
15:210-218. PEGylated proteins are currently being used in protein
replacement therapies and for other therapeutic uses. For example,
PEGylated interferon (PEG-INTRON A®) is clinically used for treating
Hepatitis B. PEGylated adenosine deaminase (ADAGEN®) is being used to
treat severe combined immunodeficiency disease (SCIDS). PEGylated
L-asparaginase (ONCAPSPAR®) is being used to treat acute
lymphoblastic leukemia (ALL). It is preferred that the covalent linkage
between the polymer and the active compound and/or the polymer: itself is
hydrolytically degradable under physiological conditions. Such conjugates
known as "prodrugs" can readily release the active compound inside the
body. Controlled release of an active compound can also be achieved by
incorporating the active ingredient into microcapsules, nanocapsules, or
hydrogels generally known in the art. Other pharmaceutically acceptable
prodrugs of the compounds of this invention include, but are not limited
to, esters, carbonates, thiocarbonates, N-acyl derivatives,
N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines,
N-Mannich bases, Schiff bases, aminoacid conjugates, phosphate esters,
metal salts and sulfonate esters.

[0366] Liposomes can also be used as carriers for the active compounds of
the present invention. Liposomes are micelles made of various lipids such
as cholesterol, phospholipids, fatty acids, and derivatives thereof.
Various modified lipids can also be used. Liposomes can reduce the
toxicity of the active compounds, and increase their stability. Methods
for preparing liposomal suspensions containing active ingredients therein
are generally known in the art. See, e.g., U.S. Pat. No. 4,522,811;
Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New
York, N.Y. (1976).

[0367] The active compounds can also be administered in combination with
another active agent that synergistically treats or prevents the same
symptoms or is effective for another disease or symptom in the patient
treated so long as the other active agent does not interfere with or
adversely affect the effects of the active compounds of this invention.
Such other active agents include but are not limited to anti-inflammation
agents, antiviral agents, antibiotics, antifungal agents, antithrombotic
agents, cardiovascular drugs, cholesterol lowering agents, anti-cancer
drugs, hypertension drugs, and the like.

[0369] The compounds of Formula (I) can be synthesized by the general
route described in Schemes 1, 2, 3 and 4.

##STR00005##

[0370] The reaction of commercially available bromoacylchlorides or
chloroacylchlorides of formula (II) with commercially available amines of
formula (III) at room temperature using dichloromethane as a solvent
leads the bromoacyl or chloroacyl derivatives of formula (IV) in high
yield. These bromoacyl or chloroacyl derivatives of formula (IV) reacts
with commercially available phenylcyclopropylamine derivatives of formula
(V) (both cis ((1S,2S) (1R,2R)) and trans ((1S,2R), (1R,2S)) versions as
well the individual diastereoisomers corresponding to (1S,2S), (1S,2R),
(1R,2S) and (1R,2R) can be used) using acetonitrile as a solvent and
diisopropylethylamine as a base resulting in the formation of the
derivatives of formula (VI), which are subject of the present invention.
The Examples below were synthesized using trans phenylcyclopropylamines
of formula (V). Alkylation of the compounds of formula (VI) using
commercially available alkylating agent of formula (VII), where --X
represents a good leaving group like an halogen atom, and cesium
carbonate as a base results in the formation of the derivatives of
formula (VIII) which are also subject of the present invention as defined
above.

[0371] On the other hand, the compounds of formula (I), where R8 is
defined as --C(O)Rz can be synthesized in an analogous manner as
described in scheme 2.

##STR00006##

[0372] The reaction of commercially available bromoesters and bromoketones
of formula (IX) with commercially available phenylcyclopropylamine
derivatives of formula (V) (including both cis ((1S,2S) (1R,2R)) and
trans ((1S,2R), (1R,2S)) versions as well the individual diastereoisomers
corresponding to (1S,2S), (1S,2R), (1R,2S) and (1R,2R) can be used) using
acetonitrile as a solvent and diisopropylethylamine as a base resulting
in the formation of the derivatives of formula (X), which are subject of
the present invention. The Examples below were synthesized using trans
phenylcyclopropylamines of formula (V). Alkylation of the compounds of
formula (X) using commercially available alkylating agent of formula
(VII), where --X is a good leaving group like halogen, and cesium
carbonate as a base results in the formation of the derivatives of
formula (XI) which are also subject of the present invention as defined
above.

[0373] The derivatives containing a Phenylcyclopropyl group substituted at
the phenyl moiety (R different from a hydrogen atom in scheme 3) can be
synthesized following the general route described in scheme 3.

##STR00007##

[0374] Commercially availables nitrostyrene of formula (XII) have been
subjected to a cyclopropanation reaction using trimetilsulfoxonium iodide
and potassium tertbutylate. The nitro group of the resulted
nitrocyclopropyl derivatives of formula (XIII) has been then reduced
using zinc in hydrochloric acid to afford the cyclopropylamino
derivatives of formula (XIV). These compounds of formula (XIV) (both cis
((1S,2S) (1R,2R)) and trans ((1S,2R), (1R,2S)) versions as well the
individual diastereoisomers corresponding to (1S,2S), (1S,2R), (1R,2S)
and (1R,2R) can be used) react with t-butyl dicarbonate at room
temperature using triethylamine as a base and dichloromethane as a
solvent leading intermediate of formula (XV) in high yield. Alkylation of
the derivatives of formula (XV) with the derivatives of formula (IV)
described earlier, using NaH as a base and DMF as a solvent, lead to the
intermediates of formula (XVI). Deprotection of the Boc-group using HCl
in Et2O lead to the formation of derivatives of formula (XVII),
which are also subjects of the present invention.

##STR00008##

[0375] The reaction of intermediate E (XIV-Br) (both cis ((1S,2S) (1R,2R))
and trans ((1S,2R), (1R,2S)) versions as well the individual
diastereoisomers corresponding to (1S,2S), (1S,2R), (1R,2S) and (1R,2R)
can be used) with 1-butyl dicarbonate at room temperature using
triethylamine as a base and tetrahydrofuran as a solvent leads to the
formation of the compounds of formula (XV-Br) in high yield. These
boc-protected derivatives (XV-Br) react with commercially available
boronic acid derivatives of formula (XVIII) using acetonitrile as a
solvent, potassium carbonate as a base and tetrakis(triphenylphospine)
paladium (0) as a catalyst resulting in the formation of the derivatives
of formula (XIX). Alkylation with bromoacyl or chloroacyl derivatives of
formula (IV), using NaH as a base and DMF as a solvent lead to the
formation of the compounds of formula (XX). Deprotection of the Boc-group
using HCl in Et2O results in the formation of the derivatives of
formula (XXI) which are also subjects of the present invention.

EXAMPLES

[0376] The program used to generate the names corresponding to the
structures in the Example compounds below was MDL ISIS Draw 2.5 (using
the ACD/Name for ISIS Draw add-in). This program named the molecules as
the (1S,2R) configuration due to the configuration of the input structure
and the "trans" term has been substituted in the place of the (1S,2R)
term specified by the program. The structures depicted below for the
Example compounds below are shown as having one particular stereochemical
configuration around the cyclopropyl carbon atoms of the
phenylcyclopropylamine core (1S,2R). All the compounds synthesized in the
Examples are mixtures having both configurations (1R,2S) and (1S,2R),
that is to say they are "trans" in respect to the cycloproyl ring of the
cyclopropyl ring system. This is due to the fact the
phenylcyclopropylamine starting material used is "trans." It is
contemplated that the cis configuration starting material or the
individual diastereomers/enantiomers could be used as starting material,
all of which are either commercially or synthetically available. Thus,
the invention relates to compounds of Formula I, I(a), and those of the
examples that have specific stereochemical configurations around the
cyclopropyl ring e.g., trans ((1R,2S) and (1S,2R)) and cis (1R,2R) and
(1S,2S). A preferred stereochemical configuration around the cyclopropyl
ring of phenylcyclopropylamine is trans.

[0377] The compounds of the examples can also be synthesized or provided
in a salt form. The skilled artisan is aware and capable of making salt
forms and/or converting salt forms of the compounds of the invention,
e.g., compounds of Formula I, I(a), and those of the Examples. In some
cases the compounds of Formula I, I(a), and the Examples can be more
stable as salt forms as compared to free base.

[0378] In reference to the synthetic schemes described herein the
following intermediates (and analogous intermediates or derivatives
thereof) can be made using the following procedures.

[0379] In reference to the chemical structures and names used herein, if
there is a conflict between the structure and the name, the structure
controls (i.e., drawing).

Intermediate A: 1-(benzyloxy)-4-[(trans)-2-nitrocyclopropyl]benzene

##STR00009##

[0381] Trimethylsulfoxonium iodide (0.62 g, 2.82 mmol) was added in
portions to a solution of t-BuOK (0.32 g, 2.82 mmol) in dry DMSO (5 mL).
After 10 min a solution of 1-(benzyloxy)-4-[(E)-2-nitrovinyl]benzene
(0.60 g, 2.35 mmol) in DMSO (5 mL) was transferred via canula and the
mixture was stirred at room temperature for 6 h. The reaction was poured
over water (10 mL) and extracted with Et2O (3×10 mL); the
organic layers were washed with brine (2×15 mL), dried over
anhydrous Na2SO4 and filtered. After removal of the solvent,
the residual orange oil was purified by column chromatography on silica
gel (5% EtOAc/hexanes) affording 0.16 g of
1-(benzyloxy)-4-[(1R,2S)-2-nitrocyclopropyl]benzene [Rf=0.5 (20%
EtOAc/hexanes), white solid, 26% yield].

Intermediate B: (Trans)-2-[4-(benzyloxy)phenyl]cyclopropanamine

##STR00010##

[0383] Zn dust (1.97 g, 30 mol) was added in small portions, over a period
of 30 min, to a vigorously stirred solution of
1-(benzyloxy)-4-[(1R,2S)-2-nitrocyclopropyl]benzene (Intermediate A, 0.81
g, 3.0 mmol) in i-PrOH (25 mL) and HCl (11 mL of aqueous solution 2.7 N,
30 mmol). After 17 h the mixture was filtered through a pad of celite,
that was washed with 10 mL of methanol. The filtrate was concentrated and
10 mL of water were added, washing with CH2Cl2 (3×15 mL).
The organic layers were dried over anhydrous Na2SO4 and
filtered. After removal of the solvent, the crude product was purified by
column chromatography on silica gel (10% MeOH/CH2Cl2) affording
0.50 g of (trans)-2-[4-(benzyloxy)phenyl]cyclopropanamine [Rf=0.2 (10%
MeOH/CH2Cl2), white solid, 70% yield].

[0386] Boc2O (1.65 equiv) was added to a solution of
(Trans)-2-[4-(benzyloxy)phenyl]cyclopropanamine (Intermediate B; 1
equiv.) and Et3N (1.65 equiv) in THF and stirred for 3 h. After
removal of the solvent, the crude residue was dissolved in EtOAc and
consecutively washed with water and HCl (10% aqueous solution) and brine.
The organic layer was dried over anhydrous Na2SO4 and filtered;
after removal of the solvent, the residue was purified by column
chromatography on silica gel (10-20% EtOAc/Hexanes), affording the
tartget compound (Yield 78%).

[0447] To a suspension of 1.5 equiv of NaH in dry DMF (10 vols) at
0° C. was added a solution of ter-butyl
(trans)-2-[4-(benzyloxy)phenyl]cyclopropylcarbamate (Intermediate C, 1
equiv) in dry DMF (2 vols) and stirr for 30 mins. Then, added was a
solution of 1-(chloroacetyl)-4-methylpiperazine (1.5 equiv) in dry DMF
(10 mL) at 0° C., stirred for 1 h at 0° C. to RT. The
progress of the reaction was monitored by TLC. After completion, reaction
mixture was poured into ice water and extracted with EtOAC. The combined
extracts were washed with water, brine, dried over anhydrous Na2SO4,
filtered and evaporated. The crude residue was purifying by preparative
HPLC to get tert-butyl
(trans)-2-[4(benzyloxy)phenyl]cyclopropyl(2-(4-methylpiperazin-1-yl)-2-ox-
oethyl)carbamate derivative.

[0448] A solution of the latter compound (1 equiv) in Et2O at 0° C.
was added Et2O.HCl slowly drop wise, stirred for 1 h at 0° C. to
RT. The progress of the reaction was monitored by TLC. After completion
reaction mixture was filtered under inert atmosphere and washed with
hexane and EtOAC, and dried under reduced pressure to get
2-((trans)-2-(1,1'-biphenyl-4-yl)cyclopropylamino)-1-(4-methylpiperazin-1-
-yl)ethanone derivative (Overall yield 21%)

[0470] A solution of tert-butyl
(trans)-2-(4-bromophenyl)cyclopropylcarbamate (Intermediate F; 1 equiv),
1.2 equiv of the boronic acid, 3.0 equiv of K2CO3 in CH3CN+H2O (4:1) was
degassed for 30 mins with Argon gas, added 0.01 equiv of Pd (PPh3)4,
heated the reaction mixture at reflux temp for 4 h. The progress of the
reaction was monitored by TLC, after completion, poured the reaction
mixture into water, extracted with EtOAc. The combined extracts were
washed with water, brine, dried over anhydrous Na2SO4, filtered and
evaporated. The crude residue was purified by column chromatography to
get tert-butyl (trans)-2-(1,1'-biphenyl-4-yl)cyclopropylcarbamate
derivative

Step-2:

[0471] To a suspension of 1.5 equiv of NaH in dry DMF (10 vols) at
0° C. was added a solution of tert-butyl
(trans)-2-(1,1'-biphenyl-4-yl)cyclopropylcarbamate derivative (1 equiv)
in dry DMF (2 vols) and stirr for 30 mins. Then, added a solution of
1-(chloroacetyl)-4-methylpiperazine (1.5 equiv) in dry DMF (10 mL) at
0° C., stirred for 1 h at 0° C. to RT. The progress of the
reaction was monitored by TLC. After completion, reaction mixture was
poured into ice water and extracted with EtOAC. The combined extracts
were washed with water, brine, dried over anhydrous Na2SO4, filtered and
evaporated. The crude residue was purifying by preparative HPLC to get
tert-butyl
(trans)-2-(1,1'-biphenyl-4-yl)cyclopropyl(2-(4-methylpiperazin-1-yl)-2-ox-
oethyl)carbamate derivative

Step-3

[0472] To a solution of tert-butyl
(trans)-2-(1,1'-biphenyl-4-yl)cyclopropyl(2-(4-methylpiperazin-1-yl)-2-ox-
oethyl)carbamate derivative (1 equiv) in Et2O at 0° C. was added
Et2O.HCl slowly drop wise, stirred for 1 h at 0° C. to RT. The
progress of the reaction was monitored by TLC. After completion reaction
mixture was filtered under inert atmosphere and washed with hexane and
EtOAC, and dried under reduced pressure to get
2-((trans)-2-(1,1'-biphenyl-4-yl)cyclopropylamino)-1-(4-methylpiperazin-1-
-yl)ethanone derivative (Overall yield 15%).

[0523] The compounds of the invention can be tested for their ability to
inhibit LSD1. The ability of the compounds of the invention to inhibit
LSD1 can be tested as follows. Human recombinant LSD1 protein was
purchased from BPS Bioscience Inc. In order to monitor LSD1 enzymatic
activity and/or its inhibition rate by our inhibitor(s) of interest,
di-methylated H3-K4 peptide (Millipore) was chosen as a substrate. The
demethylase activity was estimated, under aerobic conditions, by
measuring the release of H2O2 produced during the catalytic
process, using the Amplex® Red peroxide/peroxidase-coupled assay kit
(Invitrogen).

[0524] Briefly, a fixed amount of LSD1 was incubated on ice for 15
minutes, in the absence and/or in the presence of various concentrations
of inhibitor (from 0 to 75 μM, depending on the inhibitor strength).
Tranylcypromine (Biomol International) was used as a control for
inhibition. Within the experiment, each concentration of inhibitor was
tested in triplicate. After leaving the enzyme interacting with the
inhibitor, 12.5 μM of di-methylated H3-K4 peptide was add to each
reaction and the experiment was left for 1 hour at 37° C. in the
dark. The enzymatic reactions were set up in a 50 mM sodium phosphate, pH
7.4 buffer. At the end of the incubation, Amplex® Red reagent and
horseradish peroxidase (HPR) solution were added to the reaction
according to the recommendations provided by the supplier (Invitrogen),
and leaved to incubate for 30 extra minutes at room temperature in the
dark. A 1 μM H2O2 solution was used as a control of the kit
efficiency. The conversion of the Amplex® Red reagent to resorufin
due to the presence of H2O2 in the assay, was monitored by
fluorescence (excitation at 540 nm, emission at 590 nm) using a
microplate reader (Infinite 200, Tecan). Arbitrary units were used to
measure level of H2O2 produced in the absence and/or in the
presence of inhibitor.

[0525] The maximum demethylase activity of LSD1 was obtained in the
absence of inhibitor and corrected for background fluorescence in the
absence of LSD1. The Ki of each inhibitor was estimated at half of the
maximum activity.

[0526] In preliminary assays, a number of the compounds of the invention
were tested for their ability to inhibit LSD1 and where found to have Ki
values lower than 100 μM, including the compounds in examples 3, 6, 7
and 11. Compound of examples 1, 2, 4, 5, 9, 10, and 12 were found to have
Ki values for LSD1 of around or less than 10 μM. Schmidt et al. noted
that the IC50 values for irreversible inhibitors of LSD1 like parnate can
greatly depend on assay conditions (See Schmidt et al. (2007)
Biochemistry 46(14)4408-4416). The inventors have had a similar
experience have noticed some variations in Ki values (IC50) for the
compounds described herein in these assays due to slight variations in
assay conditions, enzyme preparations, inhibitor stability etc. Compounds
of Example 8 and 21 did not inhibit LSD1 in these assays which indicates
that large substitutions on the phenylcyclopropyl amine (R6), like the
arylalkyl group (phenyl-CH2--) of Example 21 reduce inhibitory
acitivity towards LSD1. Furthermore, when aryl groups are present in the
molecule covalently bonded to the amide nitrogen of the
phenylcyclopropylamine acetamide core (e.g, the 4-fluorophenyl group of
Example 8), such compounds appear to be inactive. Without wishing to be
boud by theory, one explanation for the lack of activity of compounds
like that of Example 8 is that they may have reduced stability. Thus,
preferred embodiments and aspects of the compounds, compositions of the
invention and their uses do not have these types of groups at these
repective positions. For example, preferred embodiments and aspects of
the invention are those where Rx and Ry are not phenyl groups
or optionally substituted phenyl groups. Preferably Rx and Ry
are groups like cycloalkyl, alkyl, and alkynyl where one of Rx and
Ry is a hydrogen atom. Additionally it is preferred that R6 is not a
large group like benzyl. It is preferred that R6 is a hydrogen atom.

[0527] Thus, the inventors have discovered a class of
phenylcyclopropylamine acetamide derivatives with surprising inhibitory
activity against LSD1. Later studies with direct comparisons to parnate
show that many of the compounds of Formula I have improved inhibitory
activity to LSD1 (see results below). Surprisingly, in view of references
such as Zirle et al. ((1962) J. Med. Chem. 1265-1284), who report that
larger substitutions on the nitrogen of tranylcypromine seem to decrease
amine oxidase inhibitory ability; the inventors have found that such
substitutions increase inhibitory activity towards LSD1. Furthermore, in
view of references such as Gooden et al. ((2008) Bioorg. Med. Chem. Let.
18:3047-3051), the inventors have surprisingly discovered modifications
to the phenylcyclopropylamine scaffold that result in LSD1 selective
inhibitors that have Ki (IC50) values for LSD1 inhibition that are lower
than that their respective Ki (IC50) values for MAO-A and/or MAO-B.

[0528] The results presented in Table 1 below shows results obtained with
compounds of the Examples (e.g., of Formula I). Parnate (2-trans
phenylcyclopropylamine) was found to have a Ki of from about 15 to 35
micromolar in the same assay depending on the enzyme preparation which is
consistent with published literature results. Furthermore, when Parnate
(e.g., tranylcypromine) was tested in the MAO-A activity assay it was
found to have an Ki (IC50) value of about 2 micromolar, when Parnate was
tested in the MAO-B activity assay it was found to have an Ki (IC50)
value of about 0.6 micromolar, both consistent with literature reported
values.

[0529] Numerous compounds of Examples were found to have Ki values for
LSD1 of less than 1 micromolar. Compounds having Ki values for LSD1 of
less than 35 micromolar are preferred compounds of the invention. Even
more preferred compounds of the invention are those that have Ki values
for LSD1 of less than 15 micromolar. Another group of more preferred
compounds of the invention are those that have a Ki value for LSD1 of
less than 1 micromolar.

Example 62

Biological Assays--Monoamine Oxidase Assays

[0530] Human recombinant monoamine oxidase proteins MAO-A and MAO-B were
purchased from Sigma Aldrich. MOAs catalyze the oxidative deamination of
1°, 2° and 3° amines. In order to monitor MAO
enzymatic activities and/or their inhibition rate by inhibitor(s) of
interest, a fluorescent-based (inhibitor)-screening assay was set up.
3-(2-Aminophenyl)-3-oxopropamamine (kynuramine dihydrobromide, Sigma
Aldrich), a non fluorescent compound was chosen as a substrate.
Kynuramine is a non-specific substrate for both MAOs activities. While
undergoing oxidative deamination by MAO activities, kynuramine is
converted into 4-hydroxyquinoline (4-HQ), a resulting fluorescent
product.

[0531] The monoamine oxidase activity was estimated by measuring the
conversion of kynuramine into 4-hydroxyquinoline. Assays were conducted
in 96-well black plates with clear bottom (Corning) in a final volume of
100 μL. The assay buffer was 100 mM HEPES, pH 7.5. Each experiment was
performed in triplicate within the same experiment.

[0532] Briefly, a fixed amount of MAO (0.25 μg for MAO-A and 0.5 μg
for MAO-B) was incubated on ice for 15 minutes in the reaction buffer, in
the absence and/or in the presence of various concentrations of inhibitor
(from 0 to 50 μM, depending on the inhibitor strength).
Tranylcypromine (Biomol International) was used as a control for
inhibition.

[0533] After leaving the enzyme(s) interacting with the inhibitor, 60 to
90 μM of kynuramine was added to each reaction for MAO-B and MAO-A
assay respectively, and the reaction was left for 1 hour at 37° C.
in the dark. The oxidative deamination of the substrate was stopped by
adding 50 μL (v/v) of NaOH 2N. The conversion of kynuramine to
4-hydroxyquinoline, was monitored by fluorescence (excitation at 320 nm,
emission at 360 nm) using a microplate reader (Infinite 200, Tecan).
Arbitrary units were used to measure levels of fluorescence produced in
the absence and/or in the presence of inhibitor.

[0534] The maximum of oxidative deamination activity was obtained by
measuring the amount of 4-hydroxyquinoline formed from kynuramine
deamination in the absence of inhibitor and corrected for background
fluorescence in the absence of MAO enzymes. The Ki of each inhibitor was
measure at Vmax/2.

[0535] Previous reports of LSD1 have found that it is involved in cell
proliferation and growth. Some studies have implicated LSD1 as a
therapeutic target for cancer. Huang et al. (2007) PNAS 104:8023-8028
found that polyamines inhibitors of LSD1 modestly cause the reexpression
of genes aberrantly silenced in cancer cells. Scoumanne et al. ((2007) J.
Biol. Chem. May 25; 282(21):15471-5) found that deficiency in LSD1 leads
to a partial cell cycle arrest in G2/M and sensitizes cells to growth
suppression induced by DNA damage. Kahl et al. ((2006) Cancer Res.
66(23):11341-7.) found that LSD1 expression is correlated with prostate
cancer aggressiveness. Metzger et al. reported that LSD1 modulation by
siRNA and pargyline regulates androgen receptor (AR) and may have
therapeutic potential in cancers where AR plays a role, like prostate,
testis, and brain cancers. Lee et al. ((2006) Chem. Biol. 13:563-567)
reported that tranylcypromie derepresses Egr-1 gene expression in some
cancer lines. A body of evidence is accumlating that Egr-1 is a tumor
suppressor gene in many contexts (see e.g., Calogero et al. (2004) Cancer
Cell International 4:1 exogenous expression of EGR-1 resulted in growth
arrest and eventual cell death in primary cancer cell lines; Lucerna et
al. (2006) Cancer Research 66, 6708-6713 show that sustained expression
of Egr-1 causes antiangiogeneic effects and inhibits tumor growth in some
models; Ferraro et al. ((2005) J. Clin. Oncol. March 20; 23(9):1921-6)
reported that Egr-1 is downregulated in lung cancer patients with a
higher risk of recurrence and may be more resistant to therapy. Other
studies have implicated LSD1 and/or histone methylation in various
cancers including kidney, lung, and breast cancer. Thus, increasing Egr-1
expression via inhibition of LSD1 is a therapeutic approach for some
cancers.

[0536] Thus, a body of evidence has implicated LSD1 in a number of
cancers, which suggests that LSD1 is a therapeutic target for cancer. The
instant inventors have discovered a class of LSD1 inhibitors that can be
used to treat diseases where LSD1 is implicated as a therapeutic target
like cancer. Accordingly, the phenylcyclopropylamine compounds of the
invention can be used to treat such diseases.

[0537] The results disclosed herein show that modifications to the
phenylpropylamine core with substituted acetamides can result in potent
LSD1 inhibitors. The examples show compounds which selectively inhibit
LSD1 compared to MAO-A and MAO-B. Thus, the inventors have discovered
unexpectedly a new class of phenylcyclopropylamine containing amine
oxidase inhibitors with activity against biologically relevant targets in
CNS conditions and oncology.

[0538] The invention therefore provides inhibitors selective for LSD1
which inhibit LSD1 to a greater extent than MAO-A and/or MAO-B in the
above described assays. Preferred LSD1 selective inhibitors have IC50
values for LSD1 which are about at least 2-fold lower than the IC50 value
for MAO-A and/or MAO-B. One example of an LSD1 selective inhibitor is
shown in Table 1 is Example 3 which has an 1050 for LSD1 which is about
at least 10-fold lower than for MAO-A and MAO-B. Another example of an
LSD1 selective inhibitor is in Example 4 which has an 1050 for LSD1 which
is more than about 5-fold lower than the 1050 for MAO-A and MAO-B. Yet
another example of a selective LSD1 inhibitor is given in Example 7 which
has an 1050 which is more than 3-fold lower for LSD1 than MAO-A and
MAO-B. Yet another example of a selective LSD1 inhibitor is given in
Example 24 which has an 1050 which is more than about 5-fold lower for
LSD1 than MAO-A and MAO-B. Yet another example of a selective LSD1
inhibitor is given in Example 36 which has an 1050 which is more than
10-fold lower for LSD1 than MAO-A and MAO-B. Yet another example of a
selective LSD1 inhibitor is given in Example 34 which has an 1050 which
is more than 10-fold lower for LSD1 than MAO-A and MAO-B. Yet another
example of a selective LSD1 inhibitor is given in Example 35 which has an
1050 which is more than 5-fold lower for LSD1 than MAO-A and MAO-B.

[0539] Furthermore, in the above described assays, the compound of Example
37 was found to have an 1050 value for LSD1 of about 29-43 nanomolar and
1050 value for MAO-B and MAO-B of greater than 40 micromolar.
Additionally, in the above described assays, the compound of Example 38
was found to have an 1050 value for LSD1 of 25 nanomolar, and MAO-B of
31.6 micromolar and MAO-A of 29.8.6 micromolar.

[0540] Particular amine oxidase inhibitors of the invention which are LSD1
selective include those of Example 26, Example 28, Example 30, and
Example 35 which all have 1050 values below 100 nanomolar and 1050 value
for MAO-A and MAO-B typically in the low micromolar range.

[0541] MAO-B inhibitors are clinically useful for treating
neurodegeneration and depression. For example, MAO-B inhibitors have been
used to treat Parkinson's disease, and have been shown to have
neuroprotective properties in some models. Therefore, the compounds of
Formula I may be used to treat such conditions, particularly where LSD1
inhibition is likely to help therapeutically. LSD1, protein complexes in
which LSD1 is a member of, and/or histone lysine methylation have been
shown to be linked a number of neurodegenerative diseases including,
Huntington's disease, Alzheimer's disease, Dementia, Lewy Body dementia,
and Frontal temporal dementia.

[0542] All publications and patent applications mentioned in the
specification are indicative of the level of those skilled in the art to
which this invention pertains. All publications and patent applications
are herein incorporated by reference to the same extent as if each
individual publication or patent application was specifically and
individually indicated to be incorporated by reference. The mere
mentioning of the publications and patent applications does not
necessarily constitute an admission that they are prior art to the
instant application.

[0543] Although the foregoing invention has been described in some detail
by way of illustration and example for purposes of clarity of
understanding, it will be obvious that certain changes and modifications
may be practiced within the scope of the appended claims.

Patent applications by Alberto Ortega Münoz, Barcelona ES

Patent applications by Julio Castro-Palomino Laria, Barcelona ES

Patent applications by Nathalie Guibourt, Barcelona ES

Patent applications by Oryzon Genomics, S.A.

Patent applications in class Having -C(=X)-, wherein X is chalcogen, bonded directly to the morpholine ring

Patent applications in all subclasses Having -C(=X)-, wherein X is chalcogen, bonded directly to the morpholine ring